Neuromodulation and associated systems and methods for the treatment of cancer

ABSTRACT

Methods for treating a human patient diagnosed with cancer with therapeutic neuromodulation and associated systems are disclosed herein. Sympathetic nerve activity can contribute to several cellular and physiological processes associated with the progression of cancer. One aspect of the present technology is directed to methods that attenuate neural traffic along target sympathetic nerves innervating tissue proximate a primary malignant tumor. Other aspects are directed to methods that at least partially inhibit sympathetic neural activity in a renal nerve of a patient diagnosed with cancer or who has a high risk of developing cancer. Targeted sympathetic nerve activity can be attenuated to improve a measurable physiological parameter corresponding to the progression of cancer in the patient. The attenuation can be achieved, for example, using an intravascularly positioned catheter carrying a therapeutic assembly, e.g., a therapeutic assembly configured to use electrically-induced, thermally-induced, and/or chemically-induced approaches to modulate the target sympathetic nerve.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/329,017, filed Apr. 28, 2016, the disclosure of whichis herein incorporated by reference in its entirety.

TECHNICAL FIELD

The present technology relates generally to methods and systems forcatheter-based neuromodulation. In particular, several embodiments aredirected to treatment of cancer and/or improving one or more measurablephysiological parameters corresponding to the progression of cancerusing neuromodulation and associated systems and methods.

BACKGROUND

Globally, cancer and cancer-related complications affect millions ofpatients every year, making cancer one of the leading internationalhealth concerns. In fact, the World Health Organization reports thatamong economically-developed nations, cancer is ranked second behindcardiovascular disease as the leading cause of death. Cancer, which isthe abnormal growth of cells in a patient's body, may have the potentialto invade or spread to other parts of the body via local spread orthrough blood or lymphatic systems to secondary tissue sites. Suchmetastatic tumors or cancer that has spread from the primary malignancysite are often the cause of cancer-related death. Typically, patientprognosis depends on a variety of aspects, including the type of cancerand location of the primary malignancy, the stage of the cancer (e.g.,size of primary malignant tumor, degree of spread from primary cancerorigin, etc.) at the time of diagnosis, the grade of the cancer (e.g.,the degree of cellular abnormality or other characteristics of thecancer cells, etc.), genetic traits/mutations and/or heterogeneity ofthe cancer, patient's age and/or health condition prior to diagnosis,and a patient's particular response to treatment. Additionally, it hasbeen demonstrated that increased stress experienced by the patient,either following diagnosis or chronic stress experienced by the patientprior to diagnosis, has a negative impact on cancer progression andoutcome.

Treatment following diagnosis is dependent on many of theabove-described factors, but generally includes surgical removal ofdetected cancerous tissue, chemotherapy regimens and other anti-canceragents, and/or radiation therapy of affected tissue. While theseconventional treatments and therapies address removal and/or killing ofcancerous cells and tissues, they can be ineffective at removing allcancerous cells from the body and in a manner that prevents metastasisand/or reoccurrence, especially in highly invasive cancers.Additionally, these primary treatments as well as long-term maintenancetherapies (e.g., hormone therapy for breast cancer patients) can causeundesirable side effects and loss of quality of life. Accordingly, thereis a need for alternative and/or adjunctive treatments that effectivelyreduce or inhibit the progression of cancer (e.g., inhibit metastasis,suspend or slow tumor growth, etc.) as well as provide better prognosisand outcomes for cancer patients with limited or no side effects.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 schematically illustrates the increase in genomic complexity asnormal epithelium of a mammary duct progresses through stages of ductalhyperplasia, ductal carcinoma in situ and ultimately toinvasive/metastatic breast cancer.

FIG. 2 is a schematic of a tumor microenvironment illustrating thecomplexity of the tumor stroma.

FIG. 3 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 4 is an enlarged anatomical view illustrating the lungs and SNSnerves associated with the anterior and posterior pulmonary plexussurrounding the pulmonary arteries.

FIG. 5 is a partially anatomical view illustrating the arterial supplyto breast tissue.

FIGS. 6A-6B are anatomical views illustrating the abdominal viscera andthe nearby nerve structures and vessels.

FIG. 6C is a partially cross-sectional view illustrating neuromodulationat a treatment location within the superior mesenteric artery inaccordance with an embodiment of the present technology.

FIG. 7 is an enlarged anatomic view of nerves of a left kidney to formthe renal plexus surrounding the left renal artery.

FIG. 8A is an anatomical view illustrating abdominal organs of a humanpatient, including a spleen, a splenic artery, and nearby organs andvessels.

FIGS. 8B and 8C are partially cross-sectional views illustratingneuromodulation at a treatment location within a splenic artery and asplenic branch artery, respectively, and in accordance with anembodiment of the present technology.

FIG. 9 is an anatomical view illustrating a portion of the uterus,vagina, an ovary and nearby organs and vessels.

FIG. 10 is a cross-sectional anatomical view illustrating a common iliacartery, an internal iliac artery, an external iliac artery, an internalpudendal artery, a superior gluteal artery and other nearby structuresand vessels.

FIG. 11A is anatomical views illustrating the testicular artery andnearby organ structures and vessels.

FIG. 11B is a partially cross-sectional view illustratingneuromodulation at a treatment location within the testicular artery inaccordance with an embodiment of the present technology.

FIG. 12 is a cross-sectional anatomical view showing a prostate, aprostatic artery, and nearby structures and vessels and illustratingneuromodulation at a treatment location within the prostatic artery inaccordance with an embodiment of the present technology.

FIG. 13 illustrates an intravascular neuromodulation system configuredin accordance with an embodiment of the present technology.

FIGS. 14A and 14B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

FIG. 15 is a block diagram illustrating a method of modulating targetsympathetic nerves in accordance with an embodiment of the presenttechnology.

FIG. 16A is a display table illustrating results from a study todetermine the effects of renal denervation on cortical axon density andmean norepinephrine concentration in animal subjects.

FIG. 16B is a series of graphs illustrating the response correlationbetween normalized cortical axon area vs. norepinephrine concentrationand norepinephrine concentration vs. extent of nerve ablation along theartery of the animal subjects of FIG. 16A.

DETAILED DESCRIPTION

The present technology is directed to apparatuses, systems, and methodsfor treating cancer and/or improving one or more measurablephysiological parameters corresponding to the progression of cancerusing neuromodulation. For example, some embodiments include performingtherapeutically-effective renal neuromodulation on a patient diagnosedwith cancer. In a particular embodiment, for example, the patient isdiagnosed with a primary malignant tumor. Other embodiments includeperforming neuromodulation of a target sympathetic nerve innervatingtissue proximate the primary malignant tumor in the patient and/or thatcontrol a function of an organ comprising the primary malignant tumor.Such organs can include the abdominal organs (e.g., pancreas, liver,kidney, stomach, gallbladder, colon, bladder, etc.) reproductive organs(e.g., testes, penis, prostate, uterus, ovaries, cervix, vulva, vagina,etc.) or other organs/location with incidences of cancer (e.g., lung,breast, etc.)

Still other embodiments include neuromodulating a target sympatheticnerve innervating a secondary tissue site in a manner that decreases arate of colonization of circulating tumor cells at the secondary tissuesite. Such secondary tissue sites may include, for example, the liver orlung. As discussed in greater detail below, neuromodulation can includerendering neural fibers inert, inactive, or otherwise completely orpartially reduced in function. This result can be electrically-induced,thermally-induced, or induced by another mechanism during aneuromodulation procedure, e.g., a procedure including percutaneoustransluminal intravascular access.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-16B. Although many of the embodimentsare described herein with respect to electrically-induced,thermally-induced, and chemically-induced approaches, other treatmentmodalities in addition to those described herein are within the scope ofthe present technology. Additionally, several other embodiments of thetechnology can have different configurations, components, or proceduresthan those described herein. A person of ordinary skill in the art,therefore, will accordingly understand that the technology can haveother embodiments with additional elements and that the technology canhave other embodiments without several of the features shown anddescribed below with reference to FIGS. 1-16B.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to the treating clinician or clinician's controldevice (e.g., a handle assembly). “Distal” or “distally” can refer to aposition distant from or in a direction away from the clinician orclinician's control device. “Proximal” and “proximally” can refer to aposition near or in a direction toward the clinician or clinician'scontrol device.

I. CANCER

A. Initiation and Progression

Generally, abnormal tissue growth, known as neoplastic tissue growth,can be benign (i.e., non-cancerous) or malignant (i.e., cancerous) whichdesignates that the neoplastic cells have the ability to invadeneighboring tissue (e.g., locally invasive) or to metastasize to asecondary location in the body (e.g., via the lymphatic system or bloodvasculature). The terms “cancer” or “cancerous” can refer to thephysiological condition in which cells have lost their ability to dividein a controlled or regulated fashion. For example, cancer can include apopulation of rapidly dividing and growing cells that progressivelyaccrues mutations in their genetic code that perturbs or evades thebody's normal mechanisms of regulation or cell death and well as allowsthe cells to invade other tissues. FIG. 1 schematically illustrates theincrease in genomic complexity as normal epithelium of a mammary ductprogresses through stages of ductal hyperplasia, ductal carcinoma insitu and ultimately to invasive/metastatic breast cancer. As cancer isattributed to the accumulation of genetic alterations in the cells, themolecular mechanisms and characterizations of these alterations havebeen a source of persistent investigation. Without being bound bytheory, studies strongly suggest that such genetic alterationsaccumulate in the cells in a stepwise manner during tumor progression(shown schematically in FIG. 1) and these transitions may, at least inpart, rely on recruitment of other cells, components, and structures tothe tumor microenvironment (Spill, F. et al., Current Opinion inBiotechnology, 2016; 40: 41-48).

Progression of human cancer from pre-malignant lesions, such asdysplasia and hyperplasia to primary malignant tumors and eventually tometastatic tumorigenesis has been clinically well recognized. Thepre-malignant lesions are caused either by genetic alterations (e.g.,initiated by mutagens) which induce monoclonal expansion of the cells,or by environmental factors, such as viral infection, which inducepolyclonal expansion of the cells. This process in which normal cellsare altered and/or become neoplastic is referred to as “tumorinitiation”. The term “tumor”, as used herein, refers to any neoplasticcell growth or proliferation, whether malignant or benign, as well as toall pre-cancerous and cancerous cells and tissues. Several types ofpre-malignant lesions can be detected in diverse organs prior to theappearance of fully malignant invasive tumors.

In the next phase of carcinogenesis, “tumor promotion” is assisted byfurther accumulation of genetic alterations occurring in one (or a few)of the pre-malignant cells, causing the cells to convert into amalignant genotype of clonal origin and to expand in number to produce aprimary tumor or mass. Typically, at this early stage of primary tumorexpansion, the cells are not invasive and metastatic; however furtheraccumulation of genetic alterations in a fraction of cells (forming newclones within the tumor) provide such cells with invasiveness andmetastatic potential. Accordingly, a primary malignant tumor isrecognized to be biologically heterogeneous with some cells beinginvasive and malignant.

During tumor initiation and promotion, cancer cells create anenvironment for their proliferation by recruiting stromal cellcomponents required for survival and growth, including fibroblasts,immune cells, pericytes, endothelial cells, nerve cells, blood vessels,and inflammatory cells (FIG. 2). “Tumor progression” then ischaracterized by increased growth speed and invasiveness of the tumorcells which is aided by these changes in the local tissuemicroenvironment. The tumor and the tumor microenvironment can becomehypoxic, which can cause further genomic instability of cancer cellswithin. Partial relief from oxygen deprivation is provided byangiogenesis. For example, tumors as well as the tumor stroma induceangiogenesis or blood vessel growth by secreting various growth factors(e.g., vascular endothelial growth factor (VEGF), basic fibroblastgrowth factor (bFGF), secretoneurin, substance P, neuropeptide Y, etc.)to encourage capillary growth into the tumor for supplying oxygen andnutrients that allow for tumor expansion. Without being bound by theory,angiogenesis of the tumor tissue and surrounding microenvironment alsoaides in removal of tumor by-products and waste as well as providinghematogenous transport for metastatically competent cancer cellsthroughout the body.

FIG. 2 is a schematic of a tumor microenvironment illustrating thecomplexity of the tumor stroma. For example, the tumor microenvironmentcomprises a mixture of carcinoma cells (e.g., migratory andnon-migratory), cells derived from hematopoietic stem cells (e.g.,macrophages, T-cells, etc.), cells derived from mesenchymal cells (e.g.,fibroblasts, myofibroblasts, mesenchymal stem cells (MSC), endothelialcells, adipocytes, etc.) and the non-cellular components of theextracellular matrix (ECM). Each of these components of the tumormicroenvironment has a role in affecting tumor progression. For example,endothelial progenitor cells (EPCs), which are recruited from the bonemarrow to the tumor stroma, are likely important in tumor progressionand are proposed to be involved in angiogenesis (e.g., incorporated inthe tumor vasculature) and in hematogenous spread of cancer cells (Gao,D., et al., Science, 2008; 319: 195-198; Nolan, D J., et al., Genes &Development, 2007; 21: 1546-1558). Secretion of VEGF recruits EPCs tothe tumor microenvironment where they in turn recruit pericytes viasecretion of platelet derived growth factor (PDGF). Together, they formnew, but leaky (e.g., having enhanced permeability) blood vessels bothin and around the growing tumor.

Referring back to FIG. 2, immune cells also populate the tumormicroenvironment. In particular, the tumor cells recruit hematopoieticmonocytes to the tumor stroma where they differentiate under theinfluence of the tumor microenvironment as tumor associated macrophages(TAMs). Once in the tumor microenvironment, these macrophages becometumor protective and facilitate metastasis. For example, TAMs secretegrowth factors (e.g., epidermal growth factor (EGF), fibroblast growthfactor (FGF)) as well as cytokines (e.g., IL-6, tumor necrosis factor(TNF)) that promote tumor growth. TAMs also promote the growth of newblood vessels via secretion of VEGF and PDGF into the tumormicroenvironment. Additionally, TAMs secrete matrix metalloproteasesthat are known to degrade and compromise the ECM, thereby permittingfurther routes of tumor cell spread. Further, TAMs produceimmunosuppressive molecules that thwart the adaptive immune system whilefurther recruiting additional TAMs to the tumor microenvironment (Noy,R., and Pollard, J. W., Immunity, 2014; 41: 49-61).

Human tissues are primarily made up of epithelial cells tethered to eachother (e.g., by immunoglobulins and cadherins) and to the ECM (e.g., byintegrins), and mesenchymal cells, which are loosely associated,pro-migratory cells. Referring back to FIG. 1, normal epithelial cellsadhere to one another to form cell layers, which act as barriers toprotect our bodies and organs from the exterior environment, while theECM (not shown) comprises a mixture of carbohydrate and proteinmolecules that provides both mechanical and biochemical support to theepithelial layers. In epithelial cancers (e.g., carcinomas), at least asubset of the malignant cancer cells can undergo anepithelial-to-mesenchymal transition (EMT), consisting of physical andgenetic changes that alter the cell's attachment structures, polarityand migratory abilities. Such migratory abilities allow these cells tobreak down or break through the ECM, endothelial structures and/orinvade nearby tissue structures. For example, once cancer cells acquirethe necessary genetic alterations to become metastatic, many have theability to penetrate the walls of lympathetic and/or blood vessels whichallows them to circulate (i.e., circulating tumor cells) to other sitesand tissues in the body. In these secondary locations, the circulatingtumor cells are able to re-penetrate the walls of the lympathetic and/orblood vessels where they can revert to epithelial cells again through amesenchymal-to-epithelial transition program and continue to multiply toform a secondary (e.g., metastatic) tumor.

B. Role of Sympathetic Nervous System

Correlative links between activation of physiological stress pathwaysand cancer progression and metastasis have been established. Forexample, chronic emotional stress, depression and/or lack of socialsupport are all associated with poorer prognosis and mortality in cancerpatients due to primary malignant tumor progression and metastasis tosecondary tissue locations (Szpunar, M. J., et al., Cancer Prev. Res.2013; 6:1262-1272). Chronic stress and/or social isolation can be aspredictive of poorer disease outcome as other standard risk factors(e.g., smoking, blood pressure, and obesity) (Lutendorf, S. K., et al.,Brain Behav Immun., 2011; 25: 250-255). In some studies, thesebiobehavioral factors are understood not to just have a role in diseaseprogression, but also to have influence on cancer onset (Lutendorf, S.K., et al., Brain Behav Immun., 2009; 23: 176-183). The potentialclinical links between stress and cancer progression have motivatedinvestigations of the influence of the SNS on cancer biology.

In response to chronic stress, cognitive and emotional information isprocessed by the central nervous system and transmitted via theperipheral nervous system to the rest of the body. The body's stressresponse involves activation of the SNS and concomitant production ofsignal mediators, such as the catecholamines norepinephrine andepinephrine, which arise both from post-ganglionic SNS terminal nervefibers and the adrenal medulla (Cole, S. W., et al., Nature Reviews,2015, 15: 563-572). As shown in FIG. 3, the SNS is a branch of theautonomic nervous system along with the enteric nervous system andparasympathetic nervous system. The SNS is a primarily involuntarybodily control system typically associated with stress responses. It isalways active at a basal level (called sympathetic tone) and becomesmore active during times of stress. The SNS regulates the function ofvirtually all human organ systems by localized release of catecholamines(e.g., norepinephrine) from sympathetic nerve terminals innervatingthese tissue and organ systems, spillover of norepinephrine fromvascular neuro-muscular junctions (the primary source of norepinephrinein plasma), and by systemic circulation of catecholamines (e.g.,epinephrine, norepinephrine) released from the adrenal gland in responseto acute, transient stress or threats. Long-term variations in basallevels as well as spikes of circulating catecholamines fromhyperactivity of the SNS responding to life circumstances can also exertmore enduring regulatory effects on gene expression by alteringconstitutive gene expression profiles in a wide variety of tissues andorgan systems.

SNS activation can release micro-molar concentrations of norepinephrineto specific and localized tissue locations when threats to homeostasisare detected (e.g., mobility of resources for microbial defense, woundhealing, etc.), and spikes in systemic catecholamine levels due to thefight-or-flight response to acute stress can transiently enhance musclestrength, accelerate heart rate; widen bronchial passages; decreasemotility (movement) of the large intestine; constrict blood vessels;increase peristalsis in the esophagus; cause pupil dilation, causepiloerection (i.e., goose bumps), cause perspiration (i.e., sweating),and raise blood pressure. Individuals with chronic, low-level stress dueto long-term exposure to adverse social circumstances (e.g., socialisolation, poverty, demanding jobs, etc.) clinically present withgreater levels of tissue and plasma norepinephrine levels than hormonalepinephrine levels (Cole, S. W., et al., Nature Reviews, 2015, 15:563-572). Gene expression modifications and resultant physiologicalchanges are mediated by activation of α-adrenergic and β-adrenergicreceptors that are differentially expressed across various tissue typesthroughout the body. Activation of adrenergic receptors bynorepinephrine, for example, initiate distinct molecular pathways andcellular changes in tissue genetic expression profiles that lend to thedetection and abilities to deal with challenges and threats from theirenvironments; however, these SNS-induced changes are also important intumor progression and metastasis as shown in experiments linkingβ-adrenergic antagonists to reduced progression of primary tumors. Forexample, the distribution of catecholamines as well as changes inrelative concentration levels paralleled alterations in activity intumor tissue via β-adrenergically linked transcription control pathwaysmediating processes such as inflammation, metastatic capacity, and cellproliferation (Cole, S. W., et al., Nature Reviews, 2015, 15: 563-572;Lutgendorf, S. K., et al., Brain Behav Immun., 2009, 23: 176-183).

Elevated catecholamine levels have been observed in both human cancerpatients as well as animal models. Many of these studies demonstratethat low social support, chronic stress, and/or depression leads toβ-adrenergic signaling and resultant activation of signalingtransduction pathways that promote biological processes involved incancer progression such as, for example, tumor cell proliferation, ECMalterations, angiogenesis, matrix metalloprotease activation,inflammatory responses and measurable increases in tumor cell invasionand metastasis (Sloan, E. K., et al., Cancer Res, 2010, 70: 7042-7052;Cole, S. W., et al., Nature Reviews, 2015, 15: 563-572). Experimentalanalysis in animal model systems and in human epidemiological studieshave shown that behavioral stress can accelerate and/or enhanceprogression of breast cancer, prostate cancer, ovarian cancer, lungcancer, stomach cancer, colorectal cancer, neuroblastomas, malignantmelanomas, pancreatic carcinoma and some hematopoietic cancers such asleukemia, among others (Cole, S. W., et al., Nature Reviews, 2015, 15:563-572; Cole, S. W. and Sood, A. K., Clin Cancer Res, 2012, 18:1201-1206; Sloan, E. K., et al., Cancer Res, 2010, 70: 7042-7052;Thaker, P. H., et al., Nature Medicine, 2006, 12: 939-944; Lutgendorf,S. K., et al., Brain Behav Immun., 2009, 23: 176-183; Lutgendorf, L. K.,et al., Brain Behav Immun., 2011, 25:250-255; Lin, Q., et al., PLoS ONE8:e61435; Al-Wadei, H. A. N., et al., Cancer Prev Res, 2012, 5:189-196).

Without being bound by theory, chronic or repetitive low-gradeSNS-activation increases norepinephrine levels within localized tissueareas as well as in systemic plasma levels and is believed to contributeto SNS-mediated regulation of cancer progression through many of themolecular and clinical changes described above. For example, the SNS maybe involved in elements of tumor initiation, tumor growth, developmentof a pro-tumor microenvironment, and cancer cell metastasis.

Experimental challenges to tumorigenesis milestones have demonstratedthe importance of β-adrenergic activation of signaling transductionpathways and, without being bound by theory, it is believed that many ofthe effects of chronic SNS activation on cancer progression involveβ-adrenergic receptor activation on cancer cells as well as severalother non-cancer cell types within the tumor microenvironment. Inpre-cancerous or cancerous cells, experimental use of β-adrenergicantagonists have shown that catecholamine activation of β-adrenergicreceptors activates known oncogenes as well as inhibits DNA repair andapoptosis in affected cells, thereby contributing to early steps incancer cell formation such as chromosomal instability and chromosomalaberrations (Cole, S. W., et al., Nature Reviews, 2015, 15: 563-572).Other studies have demonstrated the role of β-adrenergic activation inpromoting a localized inflammatory response via multiple routes. Forexample, β-adrenergic signal transduction results in transcriptionalinduction of pro-inflammatory cytokines (e.g., IL-6 and IL-8) in tumorcells as well as stimulation of tumor cells' chemotactic recruitment ofmacrophages to the tumor microenvironment. Further, norepinephrineactivation of β-adrenergic receptors on precursor monocytes stimulatesdevelopment of these immature cells in the bone marrow and spleen suchthat they can then be recruited into the tumor microenvironment, therebysignificantly increasing the density of tumor-associated macrophages(TAMs) in the tumor stroma. As stated above, TAMs promote cancer throughmultiple pathways including increased angiogenesis, ECM remodeling,chemoattraction of pro-tumor immune cells, generating a pro-inflammatoryenvironment and evasion of anti-tumor immune responses. Furtherinvolvement of the SNS in the body's immune response to tumordevelopment is the β-adrenergic-mediated inhibition of T lymphocytes andnatural killer cells as well as inhibition of the transcription of typeI and type II interferons that all play roles in cell-mediated immuneresponses against cancers.

β-adrenergic signaling is also implicated in angiogenesis within thetumor and its associated microenvironment and may be, at least in part,dependent on macrophage recruitment to the tumor. In patients withovarian cancer, poor social support has also been linked to higherlevels of norepinephrine-induced, angiogenic cytokines including VEGFand IL-6, both in peripheral blood and in the tumor microenvironment(Lutgendorf, S. K., et al., Cancer, 2002, 95: 808-815; Thaker, P. H., etal., Nature Medicine, 2006, 12: 939-944). Studies using β-adrenergicantagonists demonstrated that β-adrenergic activation was required forstress-induced increases in blood vessel density in primary malignantmammary and ovarian tumors (Thaker, P. H., et al., Nature Medicine,2006, 12: 939-944; Sloan, E. K., et al., Cancer Res, 2010, 70:7042-7052).

In addition to release of norepinephrine at or near the tumormicroenvironment, afferent (e.g., sensory) neurons may also play a rolein inducing angiogenetic progression at the tumor site. For example,release of neuropeptides, such as secretoneurin, substance P and/orneuropeptide Y, by stimulated sensory nerves are commonly associatedwith increased inflammation and pain transmission to the CNS. Thesefactors have additionally been demonstrated to have antigenic activity(Kirchmair, R., et al, Circulation, 2004, 109:777-783).

SNS influences on tumor progression also include induction of the EMTprogram in tumor cells that allow these cells to become invasive andmetastatic (Cole, S. W., et al., Nature Reviews, 2015, 15: 563-572).Further influences of the SNS on cancer cell viability includeβ-adrenergic receptor mediated resistance of programmed cell death(e.g., via anoikis and/or apoptosis). In particular, SNS activationmediates inhibition of apoptotic responses to chemotherapy-mediated celldeath, thereby attenuating the response of tumors to chemotherapy, whilefurther employing β-adrenergic signaling pathways to upregulateexpression of growth and survival factors (e.g., VEGF, IL-6, IL-8) (Wu,W., et al., et al., Biol. Pharm. Bull., 2001, 24: 772-776; Cole, S. W.,et al., Nature Reviews, 2015, 15: 563-572).

Chronic stress may also increase SNS nerve density in and around a tumorand the surrounding microenvironment. For example, chronic stress hasbeen shown to increase transcription levels of sympathetic neurotrophinnerve growth factor (NGF), which is required for the development andmaintenance of SNS nerve fibers (Sloan, E. K., et al., J Neurosci.,2007, 27: 8857-8865). Experimental studies in animal models have shownthat chronic social stress promotes growth and branching of SNS nervefibers into peripheral, tumor and lymph node tissues (Id.).Additionally, SNS nerve innervation of particular tissues and organs maymake those tissues more susceptible host environments for circulatingtumor cells to form secondary metastatic tumors in chronically stressedindividuals (Campbell, J. P., et al., PLoS Biology, 2012, 10 (e1001363):1-11; Wu, W., et al., Biol. Pharm. Bull., 2001, 24: 772-776). Forexample, stress-induced SNS activation, and resultant catecholaminerelease to bone marrow stroma, has been shown to promote breast cancercell colonization in bone marrow in animal models, and this effect wasblocked in vivo with the β-blocker propranolol (Campbell, J. P., et al.,PLoS Biology, 2012, 10 (e1001363): 1-11). In some instances, SNSactivation may upregulate expression of trophic factors and chemokines(e.g., CXCL12) that attract tumor cells to activated neural fibers(Cole, S. W., et al., Nature Reviews, 2015, 15: 563-572).

Human epidemiological and in vivo animal model studies have suggested apotential therapeutic benefit to treating cancer patients with aβ-adrenergic antagonist (i.e., β-blocker) to mitigate or assuage SNSeffects on cancer progression. However, studies have shown inconsistentresults depending on genetic profile of the tumor cells, location of thetumor, stage of tumor, and other mechanistic factors not yet identified(Cole, S. W., et al., Nature Reviews, 2015, 15: 563-572). While adjuvanttherapy using a β-blocker in certain cancer patients may be potentiallybeneficial, this therapy is limited in its ability to address alleffects of SNS activation on cancer and in all regions of the body.Particular limitations may relate to effects of SNS on cancerprogression through non-β-adrenergic receptor routes. For example, somestudies have shown that SNS activation of the α₂-adrenergic receptor instromal cells can promote breast tumor progression (Szpunar, M. J., etal., Cancer Prev Res, 2013, 6: 1262-1272). Additional limitations toβ-blocker therapy regimes include obstructed or limited access of asystemically circulating pharmaceutical agent to tumor cells, andespecially in more progressed tumor environments. As discussed earlier,vasculature of malignant tumors can have enhanced permeability resultingin a leaking effect in and around the tumor which can preclude drugaccess to cellular targets in the tumor microenvironment. Furthermore,TAMs and other inflammatory cells and byproducts can create a tissueprotective response within and around the tumor, making penetration ofpharmaceutical agents more challenging and less efficient.Interestingly, conventional cancer therapies, such as surgery,chemotherapy and radiation, can induce local or systemic inflammationtriggered by tissue injury and cancer cell death (Grivennikov, S. I., etal., Cell, 2010, 140:883-899), which in turn triggers an inflammatoryreaction analogous to a wound-healing response further heightening thechallenges associated with effective drug delivery. Additional drawbacksto use of β-adrenergic antagonists for treating a patient with cancer isthe possibility of adverse reactions associated with β-adrenoreceptorblockade (e.g., heart failure, hypotension, bradycardia, depression,insomnia, sexual dysfunction, etc.), risks associated with β-blockerintoxication (e.g., death), and management of contraindications (e.g.,concomitant use with al-adrenergic antagonists, calcium channelblockers, and other pharmaceutical cardiovascular interventions) on apatient-by-patient basis. Various aspects of the present technologyaddress SNS effects on cancer progression while overcoming thesechallenges.

II. NEUROMODULATION FOR TREATMENT OF CANCER

While sympathetic drive regulation can have adaptive utility inmaintaining homeostasis or in preparing many organs in the body for arapid response to environmental factors, chronic activation of the SNS(e.g., due to chronic stress) can drive the progression of cancerincluding, for example, tumor progression and/or metastasis. Severalembodiments of the present technology utilize intravascular devices thatreduce sympathetic nerve activity by applying, for example,radiofrequency (RF) energy to target nerve(s) or target site(s) inpatients presently diagnosed with cancer, such as a primary malignanttumor or a hematological cancer. In other embodiments, neuromodulationis used to reduce sympathetic nerve activity of an organ or other tissuestructure in patients having a high cancer risk (e.g., a predispositionor increased likelihood of developing cancer), a pre-cancerous lesion,or, in further embodiments, in patients having completed treatment forcancer and/or in remission from a previously treated cancerouscondition.

Neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the body's tissues andviscera. In particular, neuromodulation can include inhibiting,reducing, and/or blocking neural communication along target neuralfibers (i.e., efferent and/or afferent nerve fibers). Suchincapacitation can be long-term (e.g., permanent or for periods ofmonths, years, or decades) or short-term (e.g., for periods of minutes,hours, days, or weeks). While long-term disruption of the target nervescan be desirable for treating cancer patients and other sequelaeassociated with chronic stress over longer periods of time, short-termmodulation of the target nerves may also be desirable. For example, somepatients may benefit from short-term modulation to address the effectsof cancer progression, such as adjuvant therapy to increaseeffectiveness of co-administered chemotherapy drugs.

As discussed in greater detail below, neuromodulation of one or morenerve structures associated with tissue proximate a primary malignanttumor and/or that control a function of an organ comprising the primarymalignant tumor can include rendering neural fibers inert, inactive, orotherwise completely or partially reduced in function. This result canbe electrically-induced, thermally-induced, or induced by anothermechanism (e.g., chemically-induced) during a neuromodulation procedure,e.g., a procedure including percutaneous transluminal intravascularaccess.

In accordance with several aspects of the present technology,neuromodulation is used for the treatment of several forms of cancer.Non-limiting examples of forms of cancers that may be treated usingneuromodulation of targeted SNS neural fibers include carcinoma,lymphoma, blastoma, sarcoma, and leukemia. More particular examples ofsuch cancers may include, but are not limited to, breast cancer,small-cell lung cancer, non-small cell lung cancer, abdominal cancers(e.g., stomach, gastrointestinal, liver, renal/kidney, adrenal,pancreatic, colorectal, cancer of the bile duct or gall bladder, etc.),cancers associated with female reproductive organs (e.g., ovarian,uterine, cervical, endometrial, vaginal, vulvar), cancers associatedwith male reproductive organs (e.g., prostate, scrotal, testicular,penile), skin cancers (e.g., squamous cell cancer, melanoma, etc.),other pelvic cancers (e.g., bladder, ureter, urethral, anal), braincancers (e.g., glioblastoma, astrocytoma, etc.), thyroid cancer,esophageal cancer, various types of head and neck cancer (e.g., salivarygland carcinoma, oral cavity, sinus and nasal cavity, pharynx, larynx,etc.), bone cancers such as osteosarcoma, and hematopoietic and lymphoidmalignancies (e.g., leukemia, lymphoma, multiple myeloma).

As used herein, “metastatic cancer” refers to a cancer that had thepotential to, or has begun to, spread to other areas of the body. Avariety of cancers can metastasize, however, common metastasizingcancers include breast, lung, melanoma, colon, pancreatic, liver, renal,cervical, multiple myeloma, thyroid and prostate cancers. For somecancer types (e.g., primary cancer), there are common sites ofmetastases. For example, breast cancer commonly metastasizes to bonetissue, the liver, lung or the brain. The liver is also a common sitefor ovarian, colorectal, pancreatic metastasis. In a further example,lung cancer commonly metastasizes to the adrenal glands, the brain andto bone tissue. In some embodiments, SNS nerve fibers innervating one ormore of these common or likely secondary metastasis sites (e.g., tissuesor organs) can also be targeted for neuromodulation to attenuate neuraltraffic along the sympathetic nerves, for example, to decrease a rate ofcolonization of circulating tumor cells at the secondary tissue site.

As at least some of the effects of SNS activation take place early incancer progression, and in one embodiment, neuromodulation treatment canbe used in patients having a high cancer risk to reduce a) systemicplasma levels of norepinephrine from, e.g., spillover from innervationof smooth muscle surrounding blood vessels and b) localized levels ofnorepinephrine in strategic locations (e.g., tissue regions or organspresenting high cancer risk to a patient). In one embodiment, a patienthaving a pre-cancerous lesion or having other factors presenting anincreased risk of developing a precancerous or cancerous lesion in atissue region or organ can be treated with renal neuromodulation toreduce a level of renal sympathetic drive and/or reduce a level ofsystemic norepinephrine spillover in circulating plasma (Schlaich, M.P., et al., Frontiers in Physiology, 2012, 3(10): 1-7). In someembodiments, a patient having a precancerous lesion or condition canhave cells having a disordered morphology such as dysplasia or benignneoplasia. In other embodiments, pre-cancer can refer to patients havingbeen diagnosed with carcinoma in situ (e.g., an early stage,non-invasive cancer). Non-limiting examples of pre-cancerous conditionsinclude ductal carcinoma in situ, atrophic gastritis, cervicaldysplasia, leukoplakia, erythroplakia, Barrett's esophagus, adenomatouspolyps (without or without additional risk factors),

A patient presenting a high or increased cancer risk can includepatients having a family history of cancer, patients with history ofsmoking, patients exposed to high radiation levels (e.g., ionizingradiation, ultraviolet radiation), patients exposed to mutageniccompounds (e.g., asbestos), patients diagnosed with an oncovirusinfection (e.g., hepatitis C, hepatitis B, human papilloma virus,Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus,etc.) without or without other high risk factors. In other embodiments,a patient presenting a high cancer risk can have a genetic disorder ordetermined genetic pre-disposition to developing cancer. For example, acancer syndrome is a genetic disorder in which family-inherited geneticmutations in one or more genes can predispose the affected individualsto the development of particular cancers. These genetic disorders mayalso cause the early onset of these cancers, and in some cases present ahigh risk of developing independent primary tumors. Non-limitingexamples of inherited cancer-causing syndromes/genetic disorders includehereditary breast-ovarian cancer syndromes, Lynch syndrome (hereditarynonpolyposis colorectal cancer), Fanconi anemia, familial adenomatouspolyposis, hereditary paraganglioma-pheochromocytoma syndrome,Li-Faumeni syndrome, MUTYH-associated polyposis, Von Hippel-Lindaudisease, and Xeroderma pigmentosum.

Referring back to FIG. 3, the major plexuses of the SNS are aggregationsof nerves and ganglia, situated in the thoracic, abdominal, and pelviccavities, and referred to as the cardiac, celiac, and hypogastricplexuses, respectively. These nerve bundles consist not only ofsympathetic fibers derived from the ganglia, but also of nerve fibersfrom the spinal cord, which are conveyed through the white ramicommunicantes. Sympathetic efferent nerve fibers consist of bothshorter, cholinergic preganglionic fibers that synapses with longer,adrenergic postganglionic nerve fibers that travel from the ganglions tothe thoracic, abdominal, and pelvic viscera where they release, in mosttissues, the catecholamines norepinephrine and epinephrine. The generalvisceral afferent fibers also travel along the plexus branchesoriginating in the viscera, glands and blood vessels and transmittingsensory signals (e.g., pain, reflex sensation) along the neurons towardsthe central nervous system. Such organ and/or tissue afferent activitycan contribute to central sympathetic tone or drive.

Some aspects of the present technology are generally directed tomodulation of one or more nerve structures associated with tissueproximate a primary malignant tumor in the patient and/or at leastpartially disrupting communication along neural fibers that control afunction of an organ comprising a primary malignant tumor in thepatient. Certain targeted nerve structures may reside in the thoraciccavity for at least partially inhibiting sympathetic neural activityassociated with lung or breast tissues to provide a therapeuticbeneficial reduction in one or more measurable physiological parameterscorresponding to the progression and/or metastasis of lung and breastcancers, respectively. Other targeted nerve structures may be associatedwith the abdominal viscera (e.g., stomach, intestine, liver and biliarysystem, pancreas, spleen, kidneys, ureters, bladder and suprarenalglands) or reproductive organs to reduce or inhibit one or morephysiological parameters associated with progression and/or metastasisof a primary malignant tumor associated with these physiologicalstructures.

In many embodiments, modulation of targeted nerves and nerve structurescan include modulation of the nerves in locations proximate (e.g., at ornear) a percutaneously accessible artery (e.g., superior mesentericartery, the celiac artery, pulmonary artery, renal artery, ovarianartery, internal thoracic artery, etc.) or vein (e.g., superiormesenteric vein) and/or other suitable structures. Transcatheterdelivery systems can position suitable neuromodulation devices withintargeted vascular regions percutaneously as described further herein.

Selection of one or more targeted nerve and/or nerve structures can bebased on, for example, the physiological location of the primary canceror primary malignant tumor, the genetic profile of the primary tumor(e.g., specific type of cancer or other distinguishing geneticfeatures), the tumor stage or degree of progression of the primarycancer, and the overall health of the patient among other factors. Inone embodiment, treatment can include neuromodulation of one or morenerve structures associated with tissue proximate a primary malignanttumor and/or that control a function of an organ comprising the primarymalignant tumor. In other embodiments, treatment for a variety ofcancers can include renal neuromodulation to reduce sympathetic renalactivity and/or reduce central sympathetic drive (e.g., whole bodynorepinephrine spillover). In still further embodiments, treatment caninclude neuromodulation of one or more nerve structures associated witha likely secondary metastasis site, for example, to reduce a rate ofcolonization of circulating cancer cells at the secondary site. Adesirable treatment protocol may include one or more of theseneuromodulation treatments in variable combinations on apatient-by-patient basis. Several sympathetic nerve targets, treatmentlocations, and cancer types/tissue locations are listed below in TABLES1-3.

A. Thoracic Cavity Nerves and Ganglia

In vertebrates, the thoracic cavity primarily houses the lungs and themajor structures of the cardiovascular system (e.g., heart, aorta,pulmonary arteries, etc.). Examples of sympathetic nerve targets withinthe thoracic cavity are found listed in TABLE 1 and described furtherherein.

TABLE 1 THORACIC CAVITY NERVES AND GANGLIA Intravascular/IntraluminalNerve Target Treatment Location Cancer Type/Location Pulmonary plexusesPulmonary artery/vein, Decrease local Esophagus sympathetic drive totreat lung cancer Internal mammary plexus Internal thoracic artery(i.e., Decrease local (derived from the subclavian internal mammaryartery) sympathetic drive to plexus) breast parenchyma to treat breastcancer

1. Sympathetic Pulmonary Nerves

In one embodiment, modulation of one or more SNS fibers associated withthe pulmonary plexus is used to therapeutically reduce one or morephysiological parameters associated with progression of lung cancer. Thesympathetic nerves arising from primarily the thoracic spine (i.e.,levels T1-T10) with potential contribution from the cervical spine,innervate the heart and the lung after branching out from the thoracicsympathetic chain ganglia. FIG. 4 is an anatomical view illustrating thelungs 10, esophagus 12 and the major arterial vessels including, forexample, the thoracic aorta 14, the aortic arch 16, the pulmonary trunk18, the left and right pulmonary arteries 20, 21, and the left and rightpulmonary veins 22, 23. The anterior and posterior pulmonary plexuses24, 25 (referred to together as pulmonary plexus) are the sites ofconvergence of autonomic fibers which supply the lung 10 and are inclose proximity to the pulmonary arteries 20, 21.

In accordance with an embodiment of the present technology,neuromodulation (e.g., decreasing activity) of at least one sympatheticnerve innervating one or more of the pulmonary trunk 18, the left orright pulmonary arteries 20, 21, or branches thereof within a patient isanticipated to be therapeutically beneficial for treating lung cancer.In some instances, neuromodulation of the pulmonary plexus 24, 25 or oneor more nerve fibers thereof can be achieved via application of asuitable treatment modality, e.g., cryotherapeutic, direct heat,electrode-based, transducer-based, chemical-based, or another suitabletreatment modality within a target vessel as described above, or inanother embodiment, within the esophagus 12.

In some embodiments, reducing sympathetic tone innervating the pulmonaryvasculature may be useful for reducing at least one of a primarymalignant tumor growth rate in the lung, a primary malignant tumor sizein the lung, a degree of vascularization of a primary malignant tumor inthe lung and/or a number circulating tumor cells. In other embodiments,reducing sympathetic neural activity in the pulmonary plexus can includeimproving an effectiveness of chemotherapy drugs on tumor cells in thepatient. In yet a further embodiment, neuromodulation of the pulmonaryplexus may be beneficial in decreasing a rate of colonization ofcirculating tumor cells in the lungs of patients having a primary cancerdistal to the lungs (e.g., breast cancer, pancreatic cancer).

2. Sympathetic Breast Tissue Nerves

In another embodiment, neuromodulation of at least a portion of theinternal mammary plexus, which is derived from the subclavian plexus,can decrease local sympathetic drive to breast parenchyma to reduce oneor more physiological parameters associated with the progression and/ormetastasis of breast cancer. FIG. 5 a partial anatomical viewillustrating the arterial supply to the breast tissue 30. Asillustrated, blood flow to the breast tissue is provided by the internalthoracic artery 32 and branches 33 thereof via the subclavian artery 34,and by the lateral thoracic artery 36 and branches thereof via theaxillary artery 38. The internal mammary plexus (not shown) isintimately associated with the internal thoracic artery 32.

In accordance with an aspect of the present technology, neuromodulationof the internal mammary plexus can effectively reduce sympathetic toneto the breast tissue. A neuromodulation treatment device (not shown) canbe used to apply a suitable treatment modality, e.g., cryotherapeutic,direct heat, electrode-based, transducer-based, chemical-based, oranother suitable treatment modality within internal thoracic artery 32for treating breast cancer. In some embodiments, reducing sympathetictone of breast tissue may be useful for reducing at least one of amalignant breast tumor growth rate, a malignant breast tumor size, adegree of vascularization of a malignant breast tumor and/or a number ofinvasive or circulating breast tumor cells. In other embodiments,reducing sympathetic neural activity in the internal mammary plexus mayinclude improving an effectiveness of chemotherapy agents on breasttumor cells in the patient.

B. Abdominal Cavity Nerves and Ganglia

The abdominal cavity is a large body cavity that contains many organsand abdominal viscera. Particular embodiments of the present technologyare directed to neuromodulation of at least a portion of the superiormesenteric plexus, the celiac plexus, the renal plexus, and/or thehepatic plexus to therapeutically reduce one or more physiologicalparameters associated with progression of cancer associated with thepancreas, kidney, liver or other abdominal organ systems. Other aspectsof the present technology are directed to renal neuromodulation toreduce/inhibit/decrease central sympathetic tone or drive in the body toprovide a therapeutic reduction in one or more measurable physiologicalparameters corresponding the progression of cancer in the patient. Inyet further embodiments, immune system neuromodulation is used totherapeutically reduce mechanisms of inflammation and/or modulate atumor-related immune response. Examples of sympathetic nerve targetswithin the abdominal cavity are found listed in TABLE 2 and describedfurther herein.

TABLE 2 ABDOMINAL CAVITY NERVES AND GANGLIA Intravascular/IntraluminalNerve Target Treatment Location Cancer Type/Location Celiac plexusCeliac artery Decrease local sympathetic drive to treat cancer inabdominal viscera (e.g., pancreatic cancer, liver cancer, bile ductcancer and gallbladder cancer, leukemia, lymphoma, stomach cancer, smallintestine cancer, colorectal cancer, kidney cancer) Renal plexus/ Renalartery/ostium/vein 1) Decrease renal sympathetic drive to treat Renalnerve renal cancer (e.g., renal cell carcinoma, transitional cellcancer, renal sarcoma, Wilms tumor); 2) Decrease central sympatheticdrive to treat all cancer types (e.g., primary malignant tumor locatedin any tissue, leukemia, lymphoma, etc.) Afferent renal Renal pelvis,Renal calxy Decrease central sympathetic drive to treat all nerves(e.g., through ureter) cancer types Efferent renal Renal artery and/orthe renal 1) Decrease renal sympathetic drive to treat nerves brancharteries near the renal renal cancer (e.g., renal cell carcinoma,parenchyma transitional cell cancer, renal sarcoma, Wilms tumor); 2)Decrease central sympathetic drive to treat all cancer types (e.g.,primary malignant tumor located in any tissue, leukemia, lymphoma, etc.)Superior Superior mesenteric Decrease local sympathetic drive to treatmesenteric artery/vein pancreatic cancer, small intestine cancer andplexus colorectal cancer Hepatic plexus Hepatic artery Decrease localsympathetic drive to treat liver cancer, bile duct cancer andgallbladder cancer Splenic plexus Splenic artery/vein, Splenic 1)Decrease local sympathetic drive to treat branch arteries leukemia andlymphoma; 2) Decrease local sympathetic drive to spleen to treat primarymalignant tumors in other tissues to minimize TAM recruitment to tumormicroenvironment Gastric plexus Left gastric artery, Superior Decreaselocal sympathetic drive to treat mesenteric artery/vein,gastrointestinal cancers (e.g., stomach cancer, Inferior mesentericsmall intestine cancer, colorectal cancer) artery/vein PancreaticSplenic artery, Pancreatic Decrease pancreatic sympathetic drive totreat plexus arteries pancreatic cancer

1. Sympathetic Nerves of the Abdominal Viscera

The celiac plexus is a complex network of nerves located in the abdomen,where the celiac artery, superior mesenteric artery, and renal arteriesbranch from the abdominal aorta. The celiac plexus is located caudal tothe diaphragm (in an antecrural position), surrounds the origin of theceliac trunk, and comprises a dense network of ganglia (e.g., celiacganglia) and interconnecting fibers. The celiac plexus includes a numberof smaller plexuses, such as the hepatic plexus, splenic plexus, gastricplexus, pancreatic plexus and suprarenal plexus. The celiac plexus isalso known to transmit pain sensation originating from the pancreas aswell as most of the abdominal viscera with the exception of the colon,rectum and pelvic organs to the thalamus and cortex of the brain (Levyet. al. Gastrointestinal Endoscopy Clinics of North America. 2012; 22:231-47, viii). A ganglion is defined as a collection of nerve cellbodies and glial cells that are interconnected via a sense network ofneural rami and septae of connective tissue. The celiac ganglia can bedetected, for example, using endoscopic ultrasound or other techniques(e.g., CT, fluoroscopy). For example, visualized ganglia are typicallylocated adjacent to the celiac artery, anterior to the aorta, and arepredominantly oval or almond-shaped, ranging in size from 2 to 20 mm.

Neuromodulation of the celiac plexus and/or the celiac ganglia is thepartial or complete incapacitation or other effective disruption orregulation of nerves innervating the pancreas, e.g., nerves terminatingin or originating from the pancreas or in structures closely associatedwith the pancreas) and/or nerves innervating the liver, gallbladder,stomach, spleen, kidney, small intestine, ascending and transverse colonand the ovarian theca, respectively. In particular, neuromodulation ofthe celiac plexus comprises inhibiting, reducing, blocking, pacing,up-regulating, and/or down-regulating neural communication along neuralfibers (e.g., efferent and/or afferent neural fibers) innervating thepancreas, or in other embodiments, innervating the liver, gallbladder,and other abdominal organs. In other embodiments, the treatmentprocedure can target a subset of nerves of a smaller plexus within theceliac plexus, such as the hepatic plexus (e.g., along the hepaticartery), the splenic plexus (e.g., along the splenic artery), thegastric plexus (e.g., along the left gastric artery), and the pancreaticplexus (e.g., along the pancreatic artery). These targets can beintravenously accessed through femoral, brachial or radial approacheswhere a catheter could be navigated through the celiac trunk to thesubsidiary arteries (e.g., hepatic, splenic, pancreatic, etc.). Suchincapacitation, disruption, and/or regulation can be long-term (e.g.,permanent or for periods of months, years, or decades) or short-term(e.g., for periods of minutes, hours, days, or weeks).

Neuromodulation of the celiac plexus and/or the celiac ganglia isexpected to be useful in reducing various physiological parametersassociated with the progression of these diseases. Methods and systemsfor neuromodulation of the celiac plexus and/or celiac ganglia forefficaciously treating and/or reducing one or more physiologicalparameters associated with cancer progression (e.g., tumor growth, tumorvascularization, metastasis, etc.) of the abdominal viscera aredescribed herein.

Sympathetic neural activity via the nerve fibers of the celiac plexusand/or celiac ganglion, and particularly general visceral afferentnerves, are responsible for carrying pain signals as well as othersensory impulses such as reflex sensations from the abdominal viscera tothe brain in patients e.g., patients with pancreatic cancer, stomachcancer, liver cancer, bile duct cancer and gallbladder cancer, smallintestine cancer, colon cancer, kidney cancer, etc., which can in turnincrease central sympathetic activity. As such, afferent sympatheticactivity (e.g., pancreatic, hepatic, gastric, splenic, renal, colon,etc.) can contribute to central sympathetic tone or drive. Accordingly,neuromodulation of the celiac plexus and/or celiac ganglia is expectedto be useful in treating cancer in a variety of viscera by loweringcentral sympathetic activity, particularly when central sympatheticactivity is overactive or hyperactive (e.g., in conditions associatedwith central sympathetic overstimulation such as chronic stress).Accordingly, in some patients, reducing localized sympathetic drive viathe celiac plexus and/or celiac ganglia, central sympathetic drive,and/or other benefits from neuromodulation can outweigh the complete orpartial loss of nerve functionality in targeted organs.

The superior mesenteric plexus is a continuation of the lower part ofthe celiac plexus. The superior mesenteric plexus surrounds the superiormesenteric artery and divides into a number of secondary plexuses and/orgives rise to sympathetic nerve fibers innervating the pancreas, thesmall intestine, and colon in the abdomen. The superior mesentericganglion is the synapse point for one of the pre- and post-synapticnerves of the sympathetic division of the autonomous nervous system.Specifically, contributions to the superior mesenteric ganglion arisefrom TV10 and TV11, and these nerve fibers go on to innervate the smallintestine, the ascending colon and the transverse colon.

Neuromodulation of the superior mesenteric plexus and/or the superiormesenteric ganglia is the partial or complete incapacitation or othereffective disruption or regulation of nerves innervating the pancreas,e.g., nerves terminating in or originating from the pancreas or instructures closely associated with the pancreas) and/or nervesinnervating the small intestine, and ascending and transverse colon. Inparticular, neuromodulation of the superior mesenteric plexus comprisesinhibiting, reducing, blocking, pacing, up-regulating, and/ordown-regulating neural communication along neural fibers (e.g., efferentand/or afferent neural fibers) innervating the pancreas, or in otherembodiments, innervating the small intestine, and ascending andtransverse colon. Such incapacitation, disruption, and/or regulation canbe long-term (e.g., permanent or for periods of months, years, ordecades) or short-term (e.g., for periods of minutes, hours, days, orweeks).

Neuromodulation of the superior mesenteric plexus and/or the superiormesenteric ganglia is expected to be useful in treating cancerassociated with the pancreas, small intestine, and ascending andtransverse colon as well as pain associated with cancer. In particular,neuromodulation of the superior mesenteric plexus and/or the superiormesenteric ganglia is also expected to be useful in treating cancer in avariety of viscera by lowering central sympathetic activity (e.g.,particularly in conditions associated with central sympatheticoverstimulation such as chronic stress). Methods and systems forneuromodulation of the celiac plexus and/or celiac ganglia, the superiormesenteric plexus and/or the superior mesenteric ganglia forefficaciously treating cancer of the abdominal viscera, are furtherdescribed herein.

FIGS. 6A and 6B are anatomical views illustrating the abdominal viscera40 and the major arterial vessels including, for example, the aorta 41,the celiac artery 42 and the superior mesenteric artery 44. FIGS. 6A and6B also illustrate the sympathetic nerve structures that innervate theabdominal viscera 40, including the celiac plexus and/or celiac ganglion43, and the superior mesenteric plexus and/or ganglion 45. Treatmentprocedures for neuromodulation in accordance with embodiments of thepresent technology can include applying a treatment modality at one ormore treatment locations proximate a structure having a relatively highconcentration of sympathetic nerves innervating a diseased (e.g.,comprising a primary malignant tumor) or otherwise abnormal or targetedorgan (e.g., an organ having a high cancer risk, a pre-cancerous lesion,or having been previously treated for cancer). In some embodiments, forexample, at least one treatment location can be proximate a portion ofthe celiac artery 42, a branch of the celiac artery 42, an ostium of theceliac artery 42 a, and/or another suitable structure (e.g., anothersuitable structure in close association the celiac plexus and/or celiacganglion 43) in the vicinity of celiac sympathetic nerves. In otherembodiments, at least one treatment location can be proximate a portionof the superior mesenteric artery 44, a branch of the superiormesenteric artery 44, an ostium of the superior mesenteric artery 44 a,a superior mesenteric vein (not shown), and/or another suitablestructure (e.g., another suitable structure in close association thesuperior mesenteric ganglion 45) in the vicinity of superior mesentericsympathetic nerves.

FIG. 6C, for example, is a cross-sectional view illustratingneuromodulation at a treatment location within the superior mesentericartery 44. As shown in FIG. 6C, a treatment device 46 including a shaft47 and a therapeutic element 48 can be extended toward the superiormesenteric artery 44 to locate the therapeutic element 48 at thetreatment location within the superior mesenteric artery 44. Thetherapeutic element 48 can be configured for neuromodulation at thetreatment location via a suitable treatment modality, e.g.,cryotherapeutic, electrode-based, transducer-based, chemical-based, oranother suitable treatment modality. Likewise, the treatment device 46can be located at a treatment location within the celiac artery 42 (FIG.6A) for administering neuromodulation. In other embodiments,administering neuromodulation can include administering a suitabletreatment modality at more than one site, e.g., the celiac artery 42 andthe superior mesenteric artery 44, for example for modulating thesympathetic nerves innervating the pancreas or other abdominal organ.

Neuromodulation of the hepatic plexus, splenic plexus, gastric plexusand pancreatic plexus can be achieved via intravascular access to thehepatic artery, splenic artery, left gastric artery and pancreaticarteries, via access from the celiac trunk, if desired.

2. Sympathetic Renal Nerves

FIG. 7 is an enlarged anatomic view of nerves of innervating a leftkidney 50 of a patient. As FIG. 7 shows, the kidney 50 is innervated bya renal plexus 52, which is intimately associated with a renal artery54. The renal plexus 52 is an autonomic plexus that surrounds the renalartery 54 and is embedded within the adventitia of the renal artery 54.The renal plexus 52 extends along the renal artery 54 until it arrivesat the substance of the kidney 50, innervating the kidneys whileterminating in the blood vessels, the juxtaglomerular apparatus, and therenal tubules (not shown). Fibers contributing to the renal plexus 52arise from the celiac ganglion 43 (FIGS. 6A and 6B), the superiormesenteric ganglion 45 (FIGS. 6A and 6B), the aorticorenal ganglion 56and the aortic plexus (not shown). The renal plexus 52, also referred toas the renal nerve, is predominantly comprised of sympatheticcomponents. There is no (or at least very minimal) parasympatheticinnervation of the kidney 50.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord (renal sympathetic nerves arise fromT10-L2, FIG. 3). Referring to FIGS. 3, 6A, 6B and 7 together,preganglionic axons pass through the paravertebral ganglia (they do notsynapse) to become the lesser splanchnic nerve, the least splanchnicnerve, the first lumbar splanchnic nerve, and the second lumbarsplanchnic nerve, and they travel to the celiac ganglion 43, thesuperior mesenteric ganglion 45, and the aorticorenal ganglion 56.Postganglionic neuronal cell bodies exit the celiac ganglion 43, thesuperior mesenteric ganglion 45, and the aorticorenal ganglion 56 to therenal plexus 52 and are distributed to the renal vasculature.

It has previously been shown that stimulation of renal efferent nervesdirectly affects neural regulation components of renal function that areconsiderably stimulated in disease states characterized by heightenedsympathetic tone such as, for example, increased blood pressure inhypertensive patients. As provided herein, renal neuromodulation islikely to be valuable in the treatment of kidney cancer such as, forexample, renal cell carcinoma, transitional cell cancer, renal sarcomaand Wilms tumor among others. In particular, renal neuromodulation alongthe renal artery and/or within branches of the renal artery as describedin U.S. patent application Ser. No. 14/839,893, filed Aug. 28, 2015 andincorporated herein by reference in its entirety, is expected to reducerenal sympathetic drive in the kidney, thereby reducing the negativeimpact of SNS activation on aspects of kidney cancer progression. Renalneuromodulation is also likely to be particularly valuable in thetreatment of cancer in patients having one or more clinical conditionscharacterized by increased overall and particularly renal sympatheticactivity such as hypertension, metabolic syndrome, insulin resistance,diabetes, among others.

As the reduction of afferent neural signals contributes to the systemicreduction of sympathetic tone/drive, renal neuromodulation might also beuseful in treating cancers found throughout the body. For example, areduction in central sympathetic drive may reduce the incidence ofmetastasis and/or improve another measurable physiological parameterassociated with the progression of cancer, such as reducing at least oneof a primary malignant tumor growth rate, a primary malignant tumorsize, a degree of vascularization of a primary malignant tumor and/or anumber circulating tumor cells. In other embodiments, reducingsympathetic neural activity in the renal nerve and/or reducing centralsympathetic drive can include improving an effectiveness of chemotherapydrug on tumor cells in the patient. In a particular example, a reductionin central sympathetic drive may reduce a level of TAMs present in thetumor stroma and/or an overall level of inflammation present in themicroenvironment of the tumor, thereby allowing chemotherapeutic agentsaccess to tumor cells that would otherwise be protected by variousinflammatory cells (e.g., TAMs).

3. Sympathetic Nerves of the Immune System

Immune system neuromodulation is the partial or complete incapacitationor other effective disruption or regulation of immune system nerves,e.g., nerves terminating in or originating from one or more immunesystem organs (including, but not limited to, the spleen, lymph nodes,bone marrow, thymus, and other suitable organs) or in structures closelyassociated with the immune system organs. In particular, immune systemneuromodulation comprises inhibiting, reducing, blocking, pacing,upregulating, and/or downregulating neural communication along neuralfibers (e.g., efferent and/or afferent neural fibers) innervating one ormore immune system organs. Such incapacitation, disruption, and/orregulation can be long-term (e.g., permanent or for periods of months,years, or decades) or short-term (e.g., for periods of minutes, hours,days, or weeks). While long-term disruption of the immune system nervescan be desirable for alleviating symptoms and other sequelae associatedwith hematopoietic cancers and other cancers throughout the body (e.g.,to reduce a tumor-associated inflammatory response, etc.) over longerperiods of time, short-term modulation of the immune system nerves mayalso be desirable, for example, to generate a temporary reduction inimmune system function to treat a patient.

Furthermore, afferent sympathetic activity from immune system organs cancontribute to central sympathetic tone or drive. Accordingly, immunesystem neuromodulation is expected to be useful in treating cancer in amanner that reduces central sympathetic activity, particularly inconditions with central sympathetic overstimulation such as chronicstress.

Potential targets for immune system neuromodulation include nervesinnervating immune system organs such as the spleen, thymus, and lymphnodes. Among the immune system organs, the spleen can be a particularlywell-suited target for neuromodulation when treating cancer, apre-cancerous condition, or in patients with a high risk of developingcancer. In addition to acting as a blood filter and blood reserve, thespleen contains in its blood reserves half of the body's monocytes,which can mature into macrophages via β-adrenergic signaling and berecruited to the tumor site as TAMs.

FIG. 8A is an anatomical view illustrating the abdominal organs,including the spleen 60, splenic artery 61, and splenic branch arteries62. Referring to FIG. 8A, treatment procedures in accordance withembodiments of the present technology can include applying a treatmentmodality at one or more treatment locations proximate a structure havinga relatively high concentration of immune system nerves. In someembodiments, for example, the treatment locations can be proximateportions of the splenic artery 61, an ostium of the splenic artery 61, asplenic branch artery 62, an ostium of a splenic branch artery 62, thesplenic vein, an ostium of the splenic vein, or a branch of the splenicvein, another portion of a vessel or duct of an immune system organ,and/or another suitable structure.

FIGS. 8B and 8C, for example, are cross-sectional views illustrating,respectively, neuromodulation at treatment locations within the splenicartery and a splenic branch artery. As shown in FIG. 8B, a treatmentdevice 64 including a shaft 65 and a therapeutic element 66 can beextended toward the splenic artery 61 to locate the therapeutic element66 at a treatment location within the splenic artery 61. Similarly, asshown in FIG. 8C, a treatment device 67 can be extended via a shaft 68toward a splenic branch artery 62 to locate the therapeutic element 69at a treatment location within the splenic branch artery 62. Thetherapeutic element 66 or 69 can be configured for neuromodulation atthe treatment locations via a suitable treatment modality, e.g.,cryotherapeutic, direct heat, electrode-based, transducer-based,chemical-based, or another suitable treatment modality.

C. Pelvic Cavity Nerves and Ganglia

The pelvic cavity is a lower body cavity bounded on the pelvic floor bythe pelvic bones, and which contains reproductive organs, the urinarybladder as well as housing the lower portion of the colon and rectum andother interstitial tissues. Particular embodiments of the presenttechnology are directed to modulation of sympathetic nerves innervatingmale and female reproductive/genital organs to therapeutically reduceone or more physiological parameters associated with progression ofcancer associated with the male reproductive system (e.g., prostate,testes, penis) or the female reproductive system (e.g., ovaries, uterus,cervix, vulva, vagina). For example, some embodiments are directed tomodulation of at least a portion of the testicular and/or penilesympathetic nerves (e.g., sympathetic nerves along the testicularvessels, pudendal vessels or other associated structures), and/or tomodulation of at least a portion of the prostatic plexus, spermaticplexus, the lumbar plexus, the sacral plexus, the uterovaginal plexus,ovarian plexus and/or particular sympathetic nerves innervating theprostate, testes, penis, ovaries, uterus, cervix, vagina and/or vulva(e.g., perineal nerve, ilioinguinal nerve, genitofemoral nerve, pudendalnerve). Other embodiments are directed to modulation of sympatheticnerves (e.g., inferior mesenteric plexus, left colic plexus, sigmoidplexus, superior hemorrhoidal plexus, inferior hypogastric plexus,pelvic plexus, middle rectal plexus, etc.) innervating the urinarybladder, descending and/or sigmoid colon and/or rectum. Examples ofsympathetic nerve targets within the pelvic cavity are found listed inTABLE 3 and described further herein.

TABLE 3 PELVIC CAVITY NERVES AND GANGLIA Intravascular/IntraluminalNerve Target Treatment Location Cancer Type/Location Ovarian plexus/Ovarian artery/vein Decrease ovarian sympathetic drive to Ovarian nervetreat ovarian cancer; decrease local sympathetic drive to treat cancerwithin or proximate the Fallopian tube (uterine tube). Vaginal plexusBranches of the internal iliac Decrease local sympathetic drive to treat(derived from artery (e.g., vaginal arteries, vaginal cancer inferiorhypogastric vaginal venous plexus) plexus) Uterine plexus Uterine arteryDecrease local sympathetic drive to treat (derived from uterine canceror vaginal cancer inferior hypogastric plexus) Prostatic plexusProstatic arteries (derived Decrease local sympathetic drive to treat(derived from from the internal iliac artery, prostate cancer inferiorhypogastric the internal pudendal artery plexus) and middle rectalarteries), Branches of the internal iliac artery, Rectum Spermaticplexus Testicular artery/vein Decrease local sympathetic drive to treattesticular cancer Genital branch of External iliac artery/vein, Decreaselocal sympathetic drive to treat genitofemoral nerve Testicular vesselstesticular cancer, scrotal cancer, penile (Lumbar plexus ) cancer,vulvar cancer and vaginal cancer Ilioinguinal nerve Deep circumflexiliac artery Decrease local sympathetic drive to treat (Lumbar plexus)(or vein) which is a branch scrotal cancer and penile cancer of theexternal iliac artery Sacral plexus Internal iliac artery, InternalDecrease local sympathetic drive to treat iliac vein male and femalereproductive/genital cancers Pudendal nerve Internal pudendal vesselsDecrease local sympathetic drive to treat (Sacral plexus) (artery) maleand female genital cancers Perineal nerve (from Internal pudendal arteryDecrease local sympathetic drive to treat pudendal nerve) male andfemale reproductive/genital cancers Inferior mesenteric Inferiormesenteric artery, Decrease local sympathetic drive to treat plexusInferior mesenteric vein cancer associated with a primary malignanttumor in the pelvic region (urinary bladder cancer, reproductive andgenital organ cancers, Vesical plexus Superior vesical artery, Decreaselocal sympathetic drive to treat Inferior vesical artery urinary bladdercancer Left colic plexus, Branches of the inferior Decrease localsympathetic drive to treat Sigmoid plexus, mesenteric artery (e.g., Leftcancers of the descending and sigmoid Superior colic artery, Sigmoidartery, colons, and rectal cancer hemorrhoidal plexus Superiorhemorrhoidal artery) Hypogastric plexus Internal iliac artery, InternalDecrease local sympathetic drive to treat iliac vein bladder cancer,prostate cancer and other male and female reproductive/genital cancersLumbosacral plexus Internal iliac artery, Internal Decrease localsympathetic drive to treat (anterior divisions of iliac vein, theUreter, cancer associated with a primary the lumbar nerves, Superiorgluteal artery and malignant tumor in the pelvic region sacral nerves,and vein coccygeal nerve)

1. Sympathetic Nerves of the Female Reproductive System

FIG. 9 is an anatomical view illustrating a portion of the uterus 70,vagina 71, an ovary 72 and nearby organs and vessels, including anovarian artery 73, a uterine artery 74 and a vaginal artery 75.Treatment procedures for ovarian, uterine or vaginal neuromodulation inaccordance with embodiments of the present technology can includeapplying a treatment modality at one or more treatment locationsproximate a structure having a relatively high concentration of ovarian,uterine, or vaginal sympathetic nerves, respectively. In someembodiments, for example, at least one treatment location can beproximate a portion/branch/ostium of the ovarian artery 73 (or vein) forneuromodulation of an ovarian plexus, a portion/branch/ostium of theuterine artery 74 (or vein) for neuromodulation of a uterine plexus orother uterine nerve, or the vaginal artery 75 (or vein) forneuromodulation of a vaginal plexus or other vaginal nerve and/oranother suitable structure in the vicinity of sympathetic nervesinnervating the ovaries, uterus and/or vagina.

As provided herein, neuromodulation is likely to be valuable in thetreatment of ovarian cancer, uterine cancer, cervical cancer, vaginalcancer, cancer of the vulva and/or cancers associated with other femalereproductive organs and tissues (e.g., endometrial cancer). Inparticular, renal neuromodulation along the ovarian artery 73, theuterine artery 74, the vaginal artery 75 and/or within other vesselsassociated with the female reproductive organs and tissues is expectedto reduce sympathetic drive in these organs, thereby reducing the impactof SNS activation on aspects of cancer progression. As the reduction ofafferent neural signals contributes to the systemic reduction ofsympathetic tone/drive, neuromodulation of the sympathetic nervesinnervating these structures might also be useful in treating cancersfound throughout the body. For example, a reduction in centralsympathetic drive may reduce the incidence of metastasis and/or improveanother measurable physiological parameter associated with theprogression of cancer.

FIG. 10 is a cross-sectional anatomical view illustrating a common iliacartery 76, an internal iliac artery 77, an external iliac artery 78, aninternal pudendal artery 79, a superior gluteal artery 80 and othernearby structures and vessels. Treatment procedures for neuromodulationof the female (e.g., vulva, vagina, clitoris) or male (e.g., testes,penis, prostate, etc.; described further below) reproductive organs forthe treatment of cancer can include, for example, applying a treatmentmodality at one or more treatment locations proximate a structure havinga relatively high concentration of sympathetic nerves innervating thesereproductive or genital structures. In some embodiments, for example, atleast one treatment location can be proximate a portion/branch/ostium ofthe internal iliac artery 77 (or vein) for neuromodulation of a sacralplexus, a portion/branch/ostium of the external iliac artery 78 (orvein) for neuromodulation of a genital branch of a genitofemoral nerve,a portion/branch/ostium of the internal pudendal artery 79 (or vein) forneuromodulation of a pudendal nerve or perineal nerve, aportion/branch/ostium of the superior gluteal artery 80 (or vein) forneuromodulation of a lumbosacral plexus, a portion/branch/ostium of thedeep circumflex iliac artery (or vein) which is a branch of the externaliliac artery 78 for neuromodulation of a ilioinguinal nerve, and/oranother suitable structure in the vicinity of nerves innervating thefemale (or male) reproductive organs.

Neuromodulation of sympathetic nerve fibers innervating femalereproductive viscera, as described above, are expected to be useful toreduce at least one of a primary malignant tumor growth rate, a primarymalignant tumor size, and/or a degree of vascularization of a primarymalignant tumor associated with these organs and/or reduce a numbercirculating tumor cells. In other embodiments, reducing sympatheticneural activity in these sympathetic nerves and/or reducing centralsympathetic drive may improve an effectiveness of chemotherapy agents ontumor cells in the patient.

2. Sympathetic Nerves of the Male Reproductive System

Referring back to FIG. 10, treatment procedures for neuromodulation ofsympathetic nerves innervating the male reproductive organs (e.g.,testes, penis, prostate, etc.) for the treatment of cancer arecontemplated. In some embodiments, neuromodulation of a sacral plexus, agenital branch of a genitofemoral nerve, a pudendal nerve or perinealnerve, the lumbosacral plexus and/or the ilioinguinal nerve can beachieved via application of a suitable treatment modality, e.g.,cryotherapeutic, direct heat, electrode-based, transducer-based,chemical-based, or another suitable treatment modality within a targetvessel as described above. In a particular example, the pudendal nerve,which is derived from the sacral plexus, accompanies the internalpudendal vessels (e.g., internal pudendal artery 79) to innervate malegenitalia, such as the penis and the scrotum. Additional sympatheticnerves to the male reproductive organs and genitalia descend through theinferior mesenteric plexus and the inferior hypogastric plexus whichaccompany the branches of the inferior mesenteric artery (not shown) andthe internal iliac artery 77, respectively. Additional treatmentlocations for neuromodulation of sympathetic nerves innervating malereproductive organs are further described below.

FIG. 11A is a cross-sectional anatomical view illustrating a testicle90, a testicular artery 91, and nearby structures and vessels. Treatmentprocedures for testicular neuromodulation for the treatment oftesticular cancer, for example, can include applying a treatmentmodality at one or more treatment locations proximate a structure havinga relatively high concentration of sympathetic nerves innervating thetestes. In some embodiments, for example, at least one treatmentlocation can be proximate a portion of the testicular artery 91, abranch of the testicular artery 91, an ostium of the testicular artery91, an testicular vein, a branch of an testicular vein, an ostium of antesticular vein, and/or another suitable structure in the vicinity oftesticular nerves (e.g., nerves originating at the spermatic plexus, thegenital branch of the genitofemoral nerve). FIG. 11B, for example, is across-sectional view illustrating neuromodulation at a treatmentlocation within the testicular artery 91. As shown in FIG. 11B, atreatment device 92 including a shaft 93 and a therapeutic element 94can be extended toward the testicular artery 91 to locate thetherapeutic element 94 at the treatment location within the testicularartery 91. The therapeutic element 94 can be configured forneuromodulation at the treatment location via a suitable treatmentmodality, e.g., cryotherapeutic, electrode-based, transducer-based,chemical-based, or another suitable treatment modality.

FIG. 12 is a cross-sectional anatomical view illustrating a prostate 95,a prostatic artery 96, and nearby structures (e.g., urinary bladder,urethra) and vessels (e.g., capsular branches). Treatment procedures forprostatic neuromodulation for the treatment of prostate cancer, forexample, can include applying a treatment modality at one or moretreatment locations proximate a structure having a relatively highconcentration of sympathetic nerves innervating the prostate. In someembodiments, neuromodulation of the prostatic plexus which is intimatelyassociated with the prostatic arteries, which is derived from internaliliac artery 77 (FIG. 10), is expected to be useful in the treatment ofprostate cancer. FIG. 12 also shows a treatment device 97 including ashaft 98 and a therapeutic element 99 can be positioned within the leftor right prostatic artery 96 to locate the therapeutic element 99 at thetreatment location. The therapeutic element 99 can be configured forneuromodulation at the treatment location via a suitable treatmentmodality, e.g., cryotherapeutic, electrode-based, transducer-based,chemical-based, or another suitable treatment modality.

While long-term disruption of the prostatic plexus or other sympatheticnerves (e.g., pudendal nerve) may be desirable for treating certainprostate, testicular and/or penile cancer patients over longer periodsof time, short-term modulation of these nerves may also be desirable.For example, some patients may benefit from short-term modulation toaddress the effects of cancer progression; however, in certaininstances, recovery of the function of these nerves may be desirable ifside-effects such as erectile dysfunction, loss of sensation and/orincontinence are experienced.

3. Sympathetic Nerves of Non-Reproductive Pelvic Organs

Other embodiments are directed to modulation of sympathetic nerves(e.g., inferior mesenteric plexus, left colic plexus, sigmoid plexus,superior hemorrhoidal plexus, inferior hypogastric plexus, pelvicplexus, middle rectal plexus, etc.) innervating the urinary bladder,descending and/or sigmoid colon and/or rectum. Referring back to FIG.10, treatment procedures for neuromodulation of sympathetic nervesinnervating the urinary bladder 81, the descending and sigmoid colon(not shown), and the rectum 82 for the treatment of cancer in theseorgan structures are contemplated. In some embodiments, neuromodulationof a vesical plexus, which accompanies the superior vesical artery 83and inferior vesical artery 84, can be can be used in a treatment ofurinary bladder cancer. Other nerve structures (e.g., inferiormesenteric plexus, hypogastric plexus) can also be targeted in thetreatment of urinary bladder cancer and accessed via the inferiormesenteric artery (not shown) or the internal iliac artery 77.Additional sympathetic nerves (e.g., left colic plexus, sigmoid plexus,and superior hemorrhoidal plexus) that innervate the lower colonstructures (not shown) and rectum 82 can also be targeted. These nervestructures accompany the branches of the inferior mesenteric artery (notshown) and the internal iliac artery 77.

D. Neuromodulation of Target Sympathetic Nerve

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the tissues and organsdiscussed above. The purposeful application of energy (e.g., electricalenergy, thermal energy) to tissue can induce one or more desired thermalheating and/or cooling effects on localized regions along all or aportion of the target vessel and adjacent regions of the SNS nervetargets, which often lay intimately within or adjacent to the adventitiaof the target vessel. Some embodiments of the present technology, forexample, include electrode-based or transducer-based approaches, whichcan be used for therapeutically-effective neuromodulation. For example,an energy delivery element (e.g., electrode) can be configured todeliver electrical and/or thermal energy at a treatment site. Suitableenergy modalities can include, for example, RF energy (monopolar and/orbipolar), pulsed RF energy, microwave energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound,high-intensity focused ultrasound (HIFU)), laser, optical energy,magnetic energy, direct heat, radiation (e.g., infrared, visible,gamma), or other suitable energy modalities alone or in combination.Where a system uses a monopolar configuration, a return electrode orground patch fixed externally on the subject can be used. Further,electrodes (or other energy delivery elements) can be used alone or withother electrodes in a multi-electrode array. Examples of suitablemulti-electrode devices are described in U.S. patent application Ser.No. 13/281,360, filed Oct. 25, 2011, and incorporated herein byreference in its entirety. Other suitable devices and technologies aredescribed in U.S. patent application Ser. No. 13/279,330, filed Oct. 23,2011, International Patent Application No. PCT/US2015/021835, filed Mar.20, 2015, and U.S. Provisional Patent Application No. 61/932,213, filedJan. 27, 2014. Additional thermal devices are described in U.S. patentapplication Ser. No. 13/279,205, filed Oct. 21, 2011. All of theforegoing patent references are incorporated herein by reference intheir entireties.

By way of theory, targeting both general afferent and efferentsympathetic nerves (e.g., via a catheter-based approach, extracorporealultrasound) may cause beneficial effects extending well beyond affectingcancer progression in or near the target tissues and/or organs, such asreducing the number of viable circulating tumor cells and/or reducing arisk of forming a metastatic tumor at a secondary site via thecirculating tumor cells. As discussed herein, a correlation betweenstress-induced sympathetic activation on cancer progression andmetastasis has been established. There is now also evidence thatsympathetic activation results in adverse consequences on cellproliferation, tumor growth rate, angiogenesis, timing and frequency ofmetastasis, as well as effectiveness of chemotherapy drugs on theprimary malignant tumor. Additionally, chronic stress causeshyperactivity (e.g., overactivity) of the sympathetic nervous systemthroughout the body. When experiencing stress, including chronic stress,hormonal and neural information (e.g., sensory afferent input) isreceived by the CNS, which in turn further elevates sympathetic tone viaefferent signaling throughout the body. Some aspects of methods oftreating patients having cancer using sympathetic neuromodulation are atleast in part derived from the recognition described herein that thekidneys may contribute to elevated central sympathetic drive.

Several aspects of the current technology are configured to reducesympathetic nerve activity within or near tissues and/or organscomprising a primary malignant tumor. Beneficial effects of reducingtargeted sympathetic neural activity can include reducing localizedrelease of norepinephrine. Several properties of the target tissuevasculature may inform the design of treatment devices and associatedmethods for achieving target sympathetic neuromodulation, for example,via intravascular access, and impose specific design requirements forsuch devices. Specific design requirements may include percutaneouslyaccessing the vasculature (e.g., pulmonary artery/vein, internalthoracic artery, celiac artery, superior mesenteric artery, hepaticartery splenic artery, gastric artery, inferior mesenteric artery,pancreatic artery, ovarian artery, internal iliac artery and branchesthereof, uterine artery, testicular artery, external iliac artery andbranches thereof, internal pudendal vessels, hypogastric artery andbranches thereof, and superior vesical artery among others),facilitating stable contact between the energy delivery elements of suchdevices and a luminal surface or wall of the vasculature, and/oreffectively modulating the target sympathetic nerves with theneuromodulatory apparatus.

Intravascular devices that reduce sympathetic nerve activity byapplying, for example, RF energy to a treatment site in the renal arteryhave recently been shown to reduce renal sympathetic drive, renalnorepinephrine spillover, and whole body norepinephrine spillover. Renalneuromodulation is expected to reduce renal sympathetic neural activity,and since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal neuromodulationmight be useful in treating multiple cancers wherein progression and/ormetastasis is associated with systemic sympathetic hyperactivity. Forexample, as previously discussed, a reduction in central sympatheticdrive may reduce a likelihood of metastasis among other physiologicalparameters associated with a primary malignant tumor.

Accordingly, renal neuromodulation is expected to be useful in treatingcancer. The beneficial effect of renal neuromodulation with respect tocancer is expected to apply regardless of the baseline renal sympatheticneural activity or the baseline level of norepinephrine in plasma (e.g.,whole body norepinephrine spillover). For example, renal neuromodulationin accordance with embodiments of the present technology can improve oneor more measurable physiological parameters corresponding to theprogression of cancer in the patient when baseline renal sympatheticneural activity is normal, below normal, or above normal (e.g.,hyperactive or overactive). Likewise, renal neuromodulation inaccordance with additional embodiments of the present technology canimprove one or more measurable physiological parameters corresponding tothe progression of cancer in the patient when baseline centralsympathetic drive, baseline norepinephrine spillover in plasma, and/orwhole body norepinephrine spillover is normal, below normal, or abovenormal (e.g., hyperactive or overactive).

As described above with respect to the design of treatment devices andassociated methods for target sympathetic neuromodulation, severalproperties of the renal vasculature may inform the design of treatmentdevices and associated methods for achieving renal neuromodulation, forexample, via intravascular access, and impose specific designrequirements for such devices. Specific design requirements for renalneuromodulation may include accessing the renal artery, a ureter, arenal pelvis, a major renal calyx, a minor renal calyx, and/or anothersuitable structure; facilitating stable contact between the energydelivery elements of such devices and a luminal surface or wall of thesuitable targeted structure, and/or effectively modulating the renalnerves with the neuromodulatory apparatus.

III. METHODS FOR TREATMENT OF CANCER

Disclosed herein are several embodiments of methods directed totreatment of cancer and other conditions associated with an increasedrisk of developing cancer (e.g., pre-disposition to developing cancer,pre-cancerous lesions, etc.) using catheter-based neuromodulation. Themethods disclosed herein are expected to represent various advantagesover a number of conventional approaches and adjuvant therapies forreducing the effects of the SNS, and in particular overactivity orhyperactivity of the SNS, on the progression of cancer. For example, thepresent methods allow for the potential targeting of elevatedsympathetic drive, which may be a key mediator of multiple physiologicalpathways promoting progression of the disease (e.g., abnormal cellproliferation, increased growth rate of tumors, ECM remodeling,angiogenesis, tumor-protective inflammatory responses, promotion ofepithelial-to-mesenchymal transition (EMT), and other aspects related tocell invasiveness and metastasis (e.g., via lymphatic or hematogenousspread of tumor cells)). Accordingly, the methods disclosed herein areexpected provide therapeutically beneficial improvement in one or moremeasurable physiological parameters corresponding to the progression ofcancer in the patient, as well as provide for localized treatment andlimited duration treatment regimens (e.g., one-time treatment).

In certain embodiments, the methods provided herein comprise performingtargeted sympathetic neuromodulation, thereby decreasing targetsympathetic nerve activity in tissues proximate to or organs comprisinga primary malignant tumor for the purposes of being able to provide oneor more of a reduction in tumor growth rate of the primary malignanttumor in the patient, a decrease in a frequency of metastasis of theprimary malignant tumor, at least partial inhibition of vascularizationof the primary malignant tumor, a decrease in a number of metastatictumors derived from the primary malignant tumor in the patient, and anincrease effectiveness of a chemotherapy agent on cancer cells derivedfrom the primary malignant tumor. For example, targeted neuromodulationis expected to reduce a level of localized sympathetic activity, andconcomitant release of norepinephrine, in the tissues and/or organscomprising the primary cancer. Reduction of regional or localizednorepinephrine levels is expected to reduce adrenergic signalingactivation within and near the tumor stroma.

Targeted sympathetic neuromodulation may be repeated one or more timesat various intervals until a desired sympathetic nerve activity level oranother therapeutic benchmark is reached. In one embodiment, forexample, a decrease in regional or local sympathetic nerve activity maybe observed via a marker of sympathetic nerve activity in cancerpatients, such as decreased levels of plasma norepinephrine(noradrenaline) or decreased levels of localized norepinephrine assessedby tissue biopsy. Other measures or markers of sympathetic nerveactivity can include muscle sympathetic nerve activity (MSNA),norepinephrine spillover, and/or heart rate variability. In anotherembodiment, other measurable physiological parameters or markers, suchas a reduction in a growth rate of the primary malignant tumor, areduction or percent shrinkage of the primary malignant tumor, areduction in blood flow to the tumor stroma and/or maintenance orreduction in the formation of new blood vessels in the tumor stroma, areduction in cytokine levels in the patient, a reduction in pain levelperceived by the cancer patient, improved blood pressure control,improved blood glucose regulation, etc., can be used to assess efficacyof the neuromodulation treatment for cancer patients.

In certain embodiments of the methods provided herein, targetedsympathetic neuromodulation is expected to result in a change insympathetic nerve activity over a specific timeframe. For example, incertain instances of these embodiments, sympathetic nerve activitylevels are decreased over an extended timeframe, e.g., within 1 month, 2months, 3 months, 6 months, 9 months or 12 months post-neuromodulation.In further embodiments, sympathetic nerve activity levels may remain atdecreased levels over extended timeframes such as greater than 3 months,greater than 6 months, greater than 12 months or greater than 24 monthspost-neuromodulation.

In several embodiments, the methods disclosed herein may comprise anadditional step of measuring sympathetic nerve activity levels, and incertain instances of these embodiments, the methods can further comprisecomparing the activity level to a baseline activity level. Suchcomparisons can be used to monitor therapeutic efficacy and to determinewhen and if to repeat the neuromodulation procedure. In certainembodiments, a baseline sympathetic nerve activity level is derived fromthe subject undergoing treatment. For example, baseline sympatheticnerve activity levels may be measured in the subject at one or moretimepoints prior to treatment. A baseline sympathetic nerve activityvalue may represent sympathetic nerve activity at a specific timepointbefore neuromodulation, or it may represent an average activity level attwo or more timepoints prior to neuromodulation. In certain embodiments,the baseline value is based on sympathetic nerve activity immediatelyprior to treatment (e.g., after the subject has already beencatheterized). Alternatively, a baseline value may be derived from astandard value for sympathetic nerve activity observed across thepopulation as a whole or across a particular subpopulation. In certainembodiments, post-neuromodulation sympathetic nerve activity levels aremeasured in extended timeframes post-neuromodulation, e.g., 3 months, 6months, 12 months or 24 months post-neuromodulation.

In certain embodiments of the methods provided herein, the methods aredesigned to decrease sympathetic nerve activity to a target level. Inthese embodiments, the methods include a step of measuring sympatheticnerve activity levels post-neuromodulation (e.g., 6 monthspost-treatment, 12 months post-treatment, etc.) and comparing theresultant activity level to a baseline activity level as discussedabove. In certain of these embodiments, the treatment is repeated untilthe target sympathetic nerve activity level is reached. In otherembodiments, the methods are simply designed to decrease sympatheticnerve activity below a baseline level without requiring a particulartarget activity level.

In one embodiment, measured norepinephrine content (e.g., assessed viatissue and/or tumor biopsy, assessed in real-time via intravascularblood collection techniques, etc.) can be reduced (e.g., at least about5%, 10%, 20% or by at least 40%) in the patient within about threemonths after at least partially inhibiting sympathetic neural activityin nerves proximate a target vessel and innervating an organ or tissuecomprising the tumor.

In one embodiment, targeted sympathetic neuromodulation may be performedon a patient diagnosed with cancer to reduce one or more measurablephysiological parameters corresponding to progression of the cancer. Insome embodiments, for example, targeted sympathetic neuromodulation mayprevent, maintain, or reduce a tumor growth rate of the primarymalignant tumor. A reduction in the growth rate of the tumor can be, forexample, at least about 5%, 10%, 25%, 50% or a greater amount asdetermined by qualitative or quantitative analysis (e.g., ultrasound,magnetic resonance imaging (MRI), positron emission tomography (PET)scan, X-Ray, etc.) before and after (e.g., 1, 3, 6, or 12 months after)a targeted sympathetic neuromodulation procedure. In other embodiments,targeted sympathetic neuromodulation may prevent expansion of, maintain,or reduce a primary malignant tumor size in a patient. A reduction intumor size can be, for example, at least about 5%, 10%, or a greateramount as determined by qualitative or quantitative analysis (e.g.,ultrasound, MRI, PET scan, X-Ray, etc.) before and after (e.g., 1, 3, 6,or 12 months after) a targeted sympathetic neuromodulation procedure.

In addition to or instead of affecting the growth rate or size of aprimary malignant tumor in a patient, targeted sympatheticneuromodulation may efficaciously treat other measurable physiologicalparameter(s) or sequela(e) corresponding to the progression of cancer inthe patient. For example, in some embodiments, targeted sympatheticneuromodulation may decrease a frequency of metastasis of the primarymalignant tumor and/or decrease a number of metastatic tumors derivedfrom the primary malignant tumor in the patient. In a particularexample, targeted sympathetic neuromodulation may reduce a number ofcirculating cancer cells via lymphatic or hematological systems in thepatient. In one embodiment, evaluation of parameters associated withmetastasis of the primary tumor may be based on comparisons to abaseline value derived from a standard or accepted epidemiological valueestablished for patients having the same cancer form, stage and/or othermedical factors. In particular embodiments, patients may be evaluated onmetastasis-related parameters within about 6 months, a year, 2 years, upto 5 years, or a longer period following targeted sympatheticneuromodulation.

In yet other embodiments, targeted sympathetic neuromodulation may atleast partially inhibit vascularization of the primary malignant tumor.In particular examples, a reduction in local sympathetic neural activitymay prevent, maintain, or reduce formation of blood vessels and/or bloodflow within or near the tumor. A reduction in blood flow perfusion oftumors can be, for example, at least about 5%, 10%, 25%, 50% or agreater amount as determined by qualitative or quantitative analysis(e.g., PET, direct contrast-enhanced MM, perfusion computed tomography,etc.) before and after (e.g., 1, 3, 6, or 12 months after) a targetedsympathetic neuromodulation procedure.

In some embodiments, targeted sympathetic neuromodulation may prevent anincrease in, maintain, or reduce a level of tumor-associatedinflammation in the patient. Targeted sympathetic neuromodulation mayimprove (e.g., reduce a level of) markers of inflammation (e.g., IL-6,IL-8) or may improve (e.g., prevent an increase in, maintain, or reduce)a number or density of TAMs within or proximal to the tumor in apatient. These and other results may occur at various times, e.g.,directly following neuromodulation or within about 1 month, 3 months, 6months, a year, or a longer period following neuromodulation. In furtherembodiments, targeted sympathetic neuromodulation can increase aneffectiveness of one or more chemotherapy agents on cancer cells derivedfrom the primary malignant tumor. Evaluation of effectiveness ofchemotherapy agents post-neuromodulation may be assessed by comparisonto a baseline value derived from a standard or accepted epidemiologicalvalue established for patients having the same cancer form, stage and/orother medical factors, or in other embodiments by assessing othermarkers of chemotherapy efficacy, such as, tumor shrinkage andbiomarkers of increased cell death such as cellular proteases in plasma(Wiita, A. P., et al., PNAS, 2014, 111: 7594-7599). These and otherresults can occur at various times, e.g., directly following targetedsympathetic neuromodulation or within about 1 month, 3 months, 6 months,a year, or a longer period following targeted sympatheticneuromodulation.

In still further embodiments, targeted sympathetic neuromodulation mayreduce the severity and/or frequency of pain associated with the cancerin the patient. Such pain reduction can be evaluated by assessing a painlevel and/or level of function in the patient following theneuromodulation treatment procedure. For example, a patient can beassessed for pain level, quality, and/or level of function using one ormore pain measurement scales, such as a standardized Visual Analog Scale(VAS), before and post-neuromodulation treatment. In a specificembodiment, a reported level of pain (e.g., as assessed on one or morepain measurement scales known in the art), can be decreased by about 5%,about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about75%, or about 90%. In other embodiments, patients may report that nomeasurable pain is experienced following a neuromodulation procedure.

As discussed previously, the progression of cancer may be related tosympathetic overactivity and, correspondingly, the degree ofsympathoexcitation in a patient may be related to the severity of theclinical presentation of the cancer, or in other embodiments, a level ofpsychological stress, social isolation, a duration of chronic stress,and other factors. The targeted tissues and organs comprising themalignant tumor may be positioned to be both a cause (via afferent nervefibers) and a target (via efferent sympathetic nerves) of elevatedcentral sympathetic drive. In some embodiments, targeted sympatheticneuromodulation can be used to reduce central sympathetic drive in apatient diagnosed with cancer in a manner that treats the patient forthe cancer and/or improves one or more measurable physiologicalparameters associated with the progress of cancer in the patient.

In certain embodiments, renal neuromodulation is used to reduce centralsympathetic drive in a patient diagnosed with cancer in a manner thattreats the patient for the cancer and/or improves one or more measurablephysiological parameters associated with the progress of cancer in thepatient. In some embodiments, for example, MSNA can be reduced by atleast about 10% in the patient within about three months after at leastpartially inhibiting sympathetic neural activity in nerves proximate arenal artery of the kidney. Similarly, in some instances whole bodynorepinephrine spillover can be reduced at least about 20%, about 30%,about 40%, about 45%, about 50% or a greater amount in the patientwithin about three months to about 12 months after at least partiallyinhibiting sympathetic neural activity in nerves proximate a renalartery of the kidney. Additionally, measured norepinephrine content(e.g., assessed via renal biopsy, assessed in real-time viaintravascular blood collection techniques, etc.) can be reduced (e.g.,at least about 5%, 10%, or by at least 20%) in the patient within aboutthree months after at least partially inhibiting sympathetic neuralactivity in nerves proximate a renal artery innervating the kidney.

In one prophetic example, a patient diagnosed with cancer can besubjected to a baseline assessment indicating a first set of measurableparameters corresponding to characteristics of a primary malignant tumorand the tumor stroma (e.g., microenvironment). Such parameters caninclude, for example, levels of central sympathetic drive (e.g., MSNA,whole body norepinephrine spillover), measured norepinephrine content(e.g., assessed via tissue and/or tumor biopsy), tumor size, tumorgrowth rate, markers of angiogenesis (e.g., blood vessel formation,blood flow perfusion within tumor, levels of angiogenic biomarkers(VEGF, bFGF, secretoneurin, substance P, neuropeptide Y, etc.) in plasmaor tissue biopsy), markers of tumor-associated inflammation (e.g.,levels of IL-6 and/or IL-8, density of TAMs in tumor/tumor stroma),blood pressure and heart rate. Following baseline assessment, thepatient can be subjected to a renal neuromodulation procedure and/or atargeted sympathetic neuromodulation procedure (e.g., targeting SNSnerves innervating tissue proximal tumor). Such procedures can, forexample, include any of the treatment modalities described herein oranother treatment modality in accordance with the present technology.For renal neuromodulation, the treatment can be performed on nervesproximate one or both kidneys of the patient. For targeted sympatheticneuromodulation, treatment can be performed on nerves proximate multipleorgans, contralateral organ structures (e.g., lung, breast, testes,ovaries, etc.) or on multiple nerves innervating the same organ.Following the treatment (e.g., 1, 3, 6, or 12 months following thetreatment), the patient can be subjected to a follow-up assessment. Thefollow-up assessment can indicate a measurable improvement in one ormore physiological parameters corresponding to the progression ofcancer.

The methods described herein address the sympathetic excess that isthought to be an underlying factor in cancer progression in patients.Currently, there are no therapies prescribed to address the effects ofsympathetic excess on tumor progression and metastasis. Certain proposedtherapies, such as administration of β-blockers, have significantlimitations including limited efficacy, undesirable side effects and maybe subject to adverse or undesirable drug interactions when used incombination. Moreover, use of β-adrenergic antagonists may require thepatient to remain compliant with the treatment regimen over time. Incontrast, neuromodulation can be a one-time or otherwise limitedtreatment that would be expected to have durable benefits to inhibit thelong-term cancer progression and thereby achieve a favorable patientoutcome.

In some embodiments, patients diagnosed with cancer can be treated withone or more conventional therapies (e.g., surgery, chemotherapy and/orradiation) and treated with one or more neuromodulation treatments. Insome instances, patients may be treated with neuromodulation alone.However, in further embodiments, patients diagnosed with cancer can betreated with other combinations of adjuvant therapies for addressing thesympathetic excess that is thought to be an underlying factor in cancerprogression in patients. For example, combinations of therapies can betailored based on specific manifestations of the cancer in a particularpatient. In a specific example, patients having cancer can be treatedwith both adrenergic antagonist drugs, such as β-blockers (e.g.,Propranolol, Carvedilol, Labetalol, Nadolol, Timolol among others) andrenal neuromodulation and/or targeted sympathetic neuromodulation (e.g.,in a tissue region associated with primary malignant tumor).

Treatment of cancer or related conditions may refer to preventing thedisease, slowing the onset or rate of development of the disease (e.g.,primary malignant tumor), reducing the risk of developing cancer,preventing or delaying metastasis of the primary cancer, reducing orending symptoms (e.g., pain) associated with the cancer, generating acomplete or partial regression of the tumor(s), or some combinationthereof.

IV. SELECTED EXAMPLES OF NEUROMODULATION MODALITIES

As noted previously, complete or partial neuromodulation of a targetsympathetic nerve in accordance with embodiments of the presenttechnology can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable locations during a treatmentprocedure. For example, neuromodulation may be achieved using variousmodalities, including for example monopolar or bipolar RF energy, pulsedRF energy, microwave energy, laser light or optical energy, magneticenergy, ultrasound energy (e.g., intravascularly delivered ultrasound,extracorporeal ultrasound, HIFU), direct heat energy, or cryotherapeuticenergy, chemicals (e.g., drugs or other agents), or combinationsthereof. In certain embodiments, neuromodulation may utilize one or moredevices including, for example, catheter devices such as the Symplicity™catheter (Medtronic, Inc.). Other suitable thermal devices are describedin U.S. Pat. Nos. 7,653,438, 8,347,891, and U.S. patent application Ser.No. 13/279,205, filed Oct. 21, 2011, and examples of suitablemulti-electrode devices are described in U.S. patent application Ser.No. 13/281,360, filed Oct. 25, 2011, and U.S. Pat. No. 8,888,773. Otherexamples of suitable direct heat devices are described in U.S.Provisional Patent Application No. 61/789,113 filed Mar. 15, 2013, andU.S. patent application Ser. No. 14/203,933, filed Mar. 11, 2014. Thedisclosures of these applications are incorporated herein by referencein their entireties.

In those embodiments of the methods disclosed herein that utilizepartial ablation, the level of energy delivered to the target artery andsurrounding tissue may be different than the level that is normallydelivered for complete neuromodulation. For example, partialneuromodulation using RF energy may use alternate algorithms ordifferent power levels than RF energy for complete neuromodulation.Alternatively, partial neuromodulation methods may utilize the samelevel of energy, but delivered to a different depth within the tissue orto a more limited area. In certain embodiments, partial neuromodulationmay be achieved using a device that differs from a device used forcomplete neuromodulation. In certain embodiments, a particular treatmentor energy modality may be more suitable for partial neuromodulation thanother treatment or energy modalities.

In some embodiments, neuromodulation may be achieved using one or morechemical agents, such as by drug delivery. In those embodiments thatutilize partial neuromodulation, the methods may utilize the samedevices and/or drug delivery systems used for complete neuromodulation,or they may use completely different devices for energy and/or drugdelivery.

Thermal effects can include both thermal ablation and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating) to partially or completely disrupt the ability of anerve to transmit a signal. Such thermal effects can include the heatingeffects associated with electrode-based or transducer-based treatment.For example, a treatment procedure can include raising the temperatureof target neural fibers to a target temperature above a first thresholdto achieve non-ablative alteration, or above a second, higher thresholdto achieve ablation. In some embodiments, the target temperature can behigher than about body temperature (e.g., about 37° C.) but less thanabout 45° C. for non-ablative alteration, and the target temperature canbe higher than about 45° C. for ablation. More specifically, heatingtissue to a temperature between about body temperature and about 45° C.can induce non-ablative alteration, for example, via moderate heating oftarget neural fibers or vascular/luminal structures that perfuse thetarget neural fibers. In cases where vascular structures are affected,the target neural fibers can be denied perfusion resulting in necrosisof the neural tissue. For example, this may induce non-ablative thermalalteration in the fibers or structures. Heating tissue to a targettemperature higher than about 45° C. (e.g., higher than about 60° C.)can induce ablation, for example, via substantial heating of targetneural fibers or of vascular or luminal structures that perfuse thetarget fibers. In some patients, it can be desirable to heat tissue totemperatures that are sufficient to ablate the target neural fibers orthe vascular or luminal structures, but that are less than about 90° C.,e.g., less than about 85° C., less than about 80° C., or less than about75° C. Other embodiments can include heating tissue to a variety ofother suitable temperatures.

In some embodiments, complete or partial neuromodulation of a targetsympathetic nerve can include an electrode-based or transducer-basedtreatment modality alone or in combination with another treatmentmodality. Electrode-based or transducer-based treatment can includedelivering electricity and/or another form of energy to tissue at atreatment location to stimulate and/or heat the tissue in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic nerve can slow orpotentially block conduction of neural signals to produce a prolonged orpermanent reduction in sympathetic activity. A variety of suitable typesof energy, such as those mentioned above, can be used to stimulateand/or heat tissue at a treatment location. In some embodiments,neuromodulation can be conducted in conjunction with one or more othertissue modulation procedures. An element, transducer, or electrode usedto deliver this energy can be used alone or with other elements,transducers, or electrodes in a multi-element array. Furthermore, theenergy can be applied from within the body (e.g., within the vasculatureor other body lumens in a catheter-based approach or outside thevasculature using, for example, a Natural Orifice TransluminalEndoscopic Surgery or NOTES procedure) and/or from outside the body,e.g., via an applicator positioned outside the body. In someembodiments, energy can be used to reduce damage to non-targeted tissuewhen targeted tissue adjacent to the non-targeted tissue is subjected toneuromodulating cooling.

As an alternative to or in conjunction with electrode-based ortransducer-based approaches, other suitable energy delivery techniques,such as a cryotherapeutic treatment modality, can be used for achievingtherapeutically-effective neuromodulation of a target sympathetic nerve.For example, cryotherapeutic treatment can include cooling tissue at atreatment location in a manner that modulates neural function. Forexample, sufficiently cooling at least a portion of a target sympatheticnerve can slow or potentially block conduction of neural signals toproduce a prolonged or permanent reduction in sympathetic activityassociated with the target sympathetic nerve. This effect can occur as aresult of cryotherapeutic tissue damage, which can include, for example,direct cell injury (e.g., necrosis), vascular or luminal injury (e.g.,starving cells from nutrients by damaging supplying blood vessels),and/or sublethal hypothermia with subsequent apoptosis. Exposure tocryotherapeutic cooling can cause acute cell death (e.g., immediatelyafter exposure) and/or delayed cell death, e.g., during tissue thawingand subsequent hyperperfusion. Neuromodulation using a cryotherapeutictreatment in accordance with embodiments of the present technology caninclude cooling a structure proximate an inner surface of a vessel orchamber wall such that tissue is effectively cooled to a depth wheresympathetic nerves reside. For example, a cooling assembly of acryotherapeutic device can be cooled to the extent that it causestherapeutically-effective, cryogenic neuromodulation. In someembodiments, a cryotherapeutic treatment modality can include coolingthat is not configured to cause neuromodulation. For example, thecooling can be at or above cryogenic temperatures and can be used tocontrol neuromodulation via another treatment modality, e.g., to protecttissue from neuromodulating energy. Other suitable cryotherapeuticdevices are described, for example, in U.S. patent application Ser. No.13/279,330, filed Oct. 23, 2011, and incorporated herein by reference inits entirety.

Cryotherapeutic treatment can be beneficial in certain embodiments. Forexample, rapidly cooling tissue can provide an analgesic effect suchthat cryotherapeutic treatment can be less painful than other treatmentmodalities. Neuromodulation using cryotherapeutic treatment cantherefore require less analgesic medication to maintain patient comfortduring a treatment procedure compared to neuromodulation using othertreatment modalities. Additionally, reducing pain can reduce patientmovement and thereby increase operator success and/or reduce proceduralcomplications. Cryogenic cooling also typically does not causesignificant collagen tightening, and therefore is not typicallyassociated with vessel stenosis. In some embodiments, cryotherapeutictreatment can include cooling at temperatures that can cause therapeuticelements to adhere to moist tissue. This can be beneficial because itcan promote stable, consistent, and continued contact during treatment.The typical conditions of treatment can make this an attractive featurebecause, for example, patients can move during treatment, cathetersassociated with therapeutic elements can move, and/or respiration cancause organs and tissues to rise and fall and thereby move the arteriesand other structures associated with these organs and tissues. Inaddition, blood flow is pulsatile and can cause structures associatedwith the kidneys or other organs to pulse. Cryogenic adhesion also canfacilitate intravascular or intraluminal positioning, particularly inrelatively-small structures (e.g., relatively-short arteries) in whichstable intravascular or intraluminal positioning can be difficult toachieve.

The use of ultrasound energy can be beneficial in certain embodiments.Focused ultrasound is an example of a transducer-based treatmentmodality that can be delivered from outside the body (i.e.,extracorporeal). In some embodiments, focused ultrasound treatment canbe performed in close association with imaging, e.g., magneticresonance, computed tomography, fluoroscopy, ultrasound (e.g.,intravascular or intraluminal), optical coherence tomography, or anothersuitable imaging modality. For example, imaging can be used to identifyan anatomical position of a treatment location, e.g., as a set ofcoordinates relative to a reference point. The coordinates can then beentered into a focused ultrasound device configured to change thedistance from source to target, power, angle, phase, or other suitableparameters to generate an ultrasound focal zone at the locationcorresponding to the coordinates. In some embodiments, the focal zonecan be small enough to localize therapeutically-effective heating at thetreatment location while partially or fully avoiding potentially harmfuldisruption of nearby structures. To generate the focal zone, theultrasound device can be configured to pass ultrasound energy through alens, and/or the ultrasound energy can be generated by a curvedtransducer or by multiple transducers in a phased array (curved orstraight). In certain embodiments, the ultrasound device may be acatheter device with an ultrasound transducer or an array of ultrasoundtransducers on its distal tip. In other embodiments the ultrasounddevice may comprise a cylindrical transducer. In certain embodimentswherein the ultrasound device is being used to perform partial ablation,the device may include discrete and/or forward-facing transducers thatcan be rotated and inserted at specific conditions, thereby allowing formore discrete lesion formation. In other embodiments, however, theextracorporeal and/or intravascular ultrasound devices may havedifferent arrangements and/or different features.

In some embodiments, neuromodulation can be effected using achemical-based treatment modality alone or in combination with anothertreatment modality. Neuromodulation using chemical-based treatment caninclude delivering one or more chemicals (e.g., drugs or other agents)to tissue at a treatment location in a manner that modulates neuralfunction. The chemical, for example, can be selected to affect thetreatment location generally or to selectively affect some structures atthe treatment location over other structures. In some embodiments, thechemical can be guanethidine, vincristine, ethanol, phenol, aneurotoxin, or another suitable agent selected to alter, damage, ordisrupt nerves. In some embodiments, energy (e.g., light, ultrasound, oranother suitable type of energy) can be used to activate the chemicaland/or to cause the chemical to become more bioavailable. A variety ofsuitable techniques can be used to deliver chemicals to tissue at atreatment location. For example, chemicals can be delivered via one ormore needles originating outside the body or within the vasculature orother body lumens (see, e.g., U.S. Pat. No. 6,978,174, the disclosure ofwhich is hereby incorporated by reference in its entirety). In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked prior todeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a vesselwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality. Examples of such chemicals include, but are notlimited to, anesthetic agents and contrast agents.

Renal neuromodulation in conjunction with the methods and devicesdisclosed herein may be carried out at a location proximate (e.g., at ornear) a vessel or chamber wall (e.g., a wall of a renal artery, one ormore branch vessels from the renal artery, a ureter, a renal pelvis, amajor renal calyx, a minor renal calyx, and/or another suitablestructure), and the treated tissue can include tissue proximate thetreatment location. For example, with regard to a renal artery, atreatment procedure can include modulating nerves in the renal plexus,which lay intimately within or adjacent to the adventitia of the renalartery. In examples where cancer cells reside in other organs ortissues, neuromodulation of target sympathetic nerves innervating thosetissues may likewise be carried out at a location proximate (e.g., at ornear) a vessel wall, wherein the target sympathetic nerves lay within oradjacent to the adventitia of the selected vessel.

In certain embodiments, monitoring, assessing and/or determiningneuromodulation efficacy can be accomplished by detecting changes in thelevel of one or more surrogate biomarkers (e.g., a biomarker thatdirectly or indirectly correlates with sympathetic nervous activity inthe patient, a biomarker that directly or indirectly correlates withcancer progression, metastasis and/or a tumor-associated inflammatoryresponse in the patient) in plasma or urine in response toneuromodulation. Systems and method for monitoring the efficacy ofneuromodulation by measuring the levels of one or more biomarkersassociated with neuromodulation including, for example, proteins ornon-protein molecules that exhibit an increase or decrease in level oractivity in response to neuromodulation are described in, e.g.,International Patent Application No. PCT/US2013/030041, filed Mar. 8,2013, and International Patent Application No. PCT/US2015/047568, filedAug. 28, 2015, the disclosures of which are incorporated herein byreference in their entireties. In other embodiments, measured levels ofprotein or non-protein molecules (e.g., associated with norepinephrinespillover, associated with inflammatory responses, etc.) that exhibit anincrease or decrease in level or activity in response to targetedneuromodulation can be assessed pre- and post-neuromodulation in tissuebiopsies.

V. SELECTED EMBODIMENTS OF NEUROMODULATION SYSTEMS AND DEVICES

FIG. 13 illustrates a neuromodulation system 100 configured inaccordance with an embodiment of the present technology. The system 100,for example, may be used to perform therapeutically-effectiveneuromodulation of one or more target sympathetic nerves of a patientdiagnosed with cancer. The system 100 includes an intravasculartreatment device 102 operably coupled to an energy source 104 and/orconsole 130 (e.g., RF energy generator, a cryotherapy console). In theembodiment shown in FIG. 13, the treatment device 102 (e.g., a catheter)includes an elongated shaft 112 having a proximal portion 114, a handle116 at a proximal region of the proximal portion 114, and a distalportion 118 extending distally relative to the proximal portion 114. Thetreatment device 102 further includes a neuromodulation assembly ortreatment section 120 at the distal portion 118 of the shaft 112. Theneuromodulation assembly 120 can include one or more electrodes orenergy-delivery elements, a cryotherapeutic cooling assembly and/or anerve monitoring device configured to be delivered to a target bloodvessel (e.g., a target artery) in a low-profile configuration.

In one embodiment, for example, the neuromodulation assembly 120 caninclude a single electrode. In other embodiments, the neuromodulationassembly 120 may comprise a basket and a plurality of electrodes carriedby the basket. The electrodes on the basket may be spaced apart fromeach other such that each electrode is approximately 90° apart from aneighboring electrode. In yet another embodiment, the neuromodulationassembly 120 can include a balloon and a plurality of bipolar electrodescarried by the balloon. In still another embodiment, the neuromodulationassembly 120 has a plurality of electrodes arranged along an elongatedmember transformable between a low-profile, delivery configuration(e.g., contained in a delivery catheter) and an expanded, deployedconfiguration in which the elongated member has a helical/spiral shape.In any of the foregoing embodiments, the neuromodulation assembly 120may comprise one or more irrigated electrodes.

Upon delivery to a target treatment site within a blood vessel, theneuromodulation assembly 120 can be further configured to be deployedinto a treatment state or arrangement for delivering energy at thetreatment site and providing therapeutically-effectiveelectrically-induced and/or thermally-induced neuromodulation of targetneural fibers. In some embodiments, the neuromodulation assembly 120 maybe placed or transformed into the deployed state or arrangement viaremote actuation, e.g., via an actuator 117, such as a knob, pin, orlever carried by the handle 116. In other embodiments, however, theneuromodulation assembly 120 may be transformed between the delivery anddeployed states using other suitable mechanisms or techniques.

The proximal end of the neuromodulation assembly 120 can be carried byor affixed to the distal portion 118 of the elongated shaft 112. Adistal end of the neuromodulation assembly 120 may terminate with, forexample, an atraumatic rounded tip or cap. Alternatively, the distal endof the neuromodulation assembly 120 may be configured to engage anotherelement of the system 100 or treatment device 102. For example, thedistal end of the neuromodulation assembly 120 may define a passagewayfor engaging a guide wire (not shown) for delivery of the treatmentdevice using over-the-wire (“OTW”) or rapid exchange (“RX”) techniques.The treatment device 120 can also be a steerable or non-steerablecatheter device (e.g., a guide catheter) configured for use without aguide wire. Body lumens (e.g., ducts or internal chambers) can betreated, for example, by non-percutaneously passing the shaft 112 andneuromodulation assembly 120 through externally accessible passages ofthe body or other suitable methods.

The console 130 can be configured to generate a selected form andmagnitude of energy for delivery to the target treatment site via theneuromodulation assembly 120. A control mechanism, such as a foot pedal132, may be connected (e.g., pneumatically connected or electricallyconnected) to the console 130 to allow an operator to initiate,terminate and, optionally, adjust various operational characteristics ofthe console 130, including, but not limited to, power delivery. Thesystem 100 may also include a remote control device (not shown) that canbe positioned in a sterile field and operably coupled to theneuromodulation assembly 120. The remote control device can beconfigured to allow for selective activation of the neuromodulationassembly 120. In other embodiments, the remote control device may bebuilt into the handle assembly 116. The energy source 104 can beconfigured to deliver the treatment energy via an automated controlalgorithm 134 and/or under the control of the clinician. In addition,the energy source 104 may include one or more evaluation or feedbackalgorithms 136 to provide feedback to the clinician before, during,and/or after therapy.

The energy source 104 can further include a device or monitor that mayinclude processing circuitry, such as a microprocessor, and a display138. The processing circuitry may be configured to execute storedinstructions relating to the control algorithm 134. The energy source104 may be configured to communicate with the treatment device 102(e.g., via a cable 106) to control the neuromodulation assembly and/orto send signals to or receive signals from the nerve monitoring device.The display 138 may be configured to provide indications of power levelsor sensor data, such as audio, visual or other indications, or may beconfigured to communicate information to another device. For example,the console 130 may also be configured to be operably coupled to acatheter lab screen or system for displaying treatment information, suchas nerve activity before and/or after treatment.

In certain embodiments, a neuromodulation device for use in the methodsdisclosed herein may combine two or more energy modalities. For example,the device may include both a hyperthermic source of ablative energy anda hypothermic source, making it capable of, for example, performing bothRF neuromodulation and cryo-neuromodulation. The distal end of thetreatment device may be straight (for example, a focal catheter),expandable (for example, an expanding mesh or cryoballoon), or have anyother configuration. For example, the distal end of the treatment devicecan be at least partially helical/spiral in the deployed state.Additionally or alternatively, the treatment device may be configured tocarry out one or more non-ablative neuromodulatory techniques. Forexample, the device may comprise a means for diffusing a drug orpharmaceutical compound at the target treatment area (e.g., a distalspray nozzle).

VI. SELECTED EXAMPLES OF TREATMENT PROCEDURES FOR NEUROMODULATION

A. Achieving Intravascular Access to the Target Vessels

In accordance with the present technology, neuromodulation of a targetsympathetic nerve, which is intimately associated with a target bloodvessel (e.g., target artery), may be achieved through intravascularaccess. As FIG. 14A shows, blood moved by contractions of the heart isconveyed from the left ventricle of the heart by the aorta. The aortadescends through the thorax and bifurcates at the left and right iliacarteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 14B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. Above the renal veins, the inferior vena cava ascends toconvey blood into the right atrium of the heart. From the right atrium,the blood is pumped through the right ventricle into the lungs, where itis oxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, where the catheter maybe placed into a target vessel (e.g., celiac artery 42, superiormesenteric artery 44, renal artery 54) for the management and/ortreatment of cancer associated with the abdominal viscera 40 (FIGS.6A-6B) and kidneys 50 (FIG. 7). This route comprises an intravascularpath that offers minimally invasive access to a respective celiacartery, superior mesenteric artery, renal artery and/or other bloodvessels (e.g., superior mesenteric vein, not shown) associated with theabdominal cavity and an intravascular pathway to some vessel targetsassociated with the pelvic cavity (e.g., inferior mesenteric artery) andthe thoracic cavity (e.g., internal thoracic artery). Alternatively, thewrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery orvein may be utilized to provide an intravascular path to thoracic vesseltargets (e.g., pulmonary artery, internal thoracic artery) as well as tothe abdominal vessel targets. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the celiacand/or superior mesenteric arteries using standard angiographictechnique.

Catheters introduced via the femoral artery route can also access thearterial vasculature associated with the pelvic cavity (see, e.g., TABLE3, treatment locations). Referring back to FIGS. 14A and 14B, a cathetermay be inserted percutaneously into the femoral artery through thisaccess site, passed through the iliac artery and aorta, and placed intoeither the left or right testicular artery 91 (FIG. 11A) forneuromodulation of the spermatic plexus such as for the managementand/or treatment of cancer associated with the testes 90 (FIGS. 11A and11B). For the management and/or treatment of cancer associated with thereproductive organs in males (e.g., testes, scrotum and penis) or infemales (e.g., cervix, vagina and vulva), neuromodulation of a genitalbranch of genitofemoral nerve, which is intimately associated with anexternal iliac artery 78 (FIG. 10), may also be achieved throughintravascular access by percutaneously inserting a catheter into eitherthe left or right femoral artery (FIG. 14A), into the respective left orright common iliac artery 76 (FIGS. 10 and 14A) and down into theexternal iliac artery 78 (FIG. 10). Further, neuromodulation of theilioinguinal nerve may also be achieved by accessing the deep circumflexiliac artery off of the external iliac artery 78 (FIG. 10). Additionaltargets for the management/treatment of cancer associated with male andfemale genitalia/reproductive organs include the sacral plexus andhypogastric plexus, which are intimately associated with a left and/orright internal iliac artery 77 (FIG. 10) or vein, and the pudendal andperineal nerves, both of which are intimately associated with leftand/or right internal pudendal arteries 79 (FIG. 10) and veins.Percutaneous intravascular access to these nerve structures can includepassing a catheter through the left or right femoral artery (FIG. 14A),into the respective left or right common iliac artery 76 (FIGS. 10 and14A) and down into the internal iliac artery 77 (FIG. 10) and into theinternal pudendal artery 79 (FIG. 10), if desired. Additional targetsfor the management/treatment of urinary bladder cancer include thevesical plexus, which is intimately associated with the superior vesicalartery 83 and inferior vesical artery 84 (FIG. 10). Percutaneousintravascular access to the vesical plexus can include passing acatheter through the left or right femoral artery (FIG. 14A), into therespective left or right common iliac artery 76 (FIGS. 10 and 14A), downinto the internal iliac artery 77 (FIG. 10) and into the superiorvesical and inferior vesical arteries 83, 84 (FIG. 10).

In accordance with a further embodiment of the present technology,neuromodulation of a left or right vaginal plexus, which is intimatelyassociated with a left or right vaginal artery 75 (FIG. 9), andneuromodulation of a left or right uterine plexus, which is intimatelyassociated with a left or right uterine artery 74 (FIG. 9) may beachieved through intravascular access. Referring to FIGS. 9, 14A, and14B together, a catheter (not shown) may be inserted percutaneously intothe left or right femoral artery through this access site, passedthrough the left or right iliac artery and the internal iliac artery,respectively, and placed into either the left or right vaginal artery 75or uterine artery 74 (FIG. 9) for the management and/or treatment ofcancer associated with the vagina 71 or uterus 70, respectively (FIG.9).

In accordance with yet a further embodiment of the present technology,neuromodulation of a left or right ovarian plexus or nerve, which isintimately associated with a left or right ovarian artery 73 (FIG. 9)may be achieved through intravascular access. Referring to FIGS. 9, 14Aand 14B together, a catheter (not shown) may be inserted in the left orright femoral artery through this access site, passed through the leftor right iliac artery and aorta, and placed into either the left orright ovarian artery 73 (FIG. 9). This route comprises an intravascularpath that offers minimally invasive access to a respective ovarianartery 73 and/or other ovarian blood vessels. Another location forintroduction of a catheter in the arterial system is through the femoralartery (as described above), passed through to the internal iliacartery, through the uterine artery 74, to the ovarian artery 73.Alternatively, the wrist, upper arm, and shoulder region provide otherlocations for introduction of catheters into the arterial system. Forexample, catheterization of either the radial, brachial, or axillaryartery may be utilized in select cases. Catheters introduced via theseaccess points may be passed through the subclavian artery on the leftside (or via the subclavian and brachiocephalic arteries on the rightside), through the aortic arch, down the descending aorta and into theovarian arteries 73 using standard angiographic technique.

In another embodiment, neuromodulation of the prostatic plexus, which isintimately associated with prostatic arteries 96 (FIG. 12), may beachieved through intravascular access. Referring to FIGS. 12, 14A and14B together, a treatment device 97 may be inserted in the left or rightfemoral artery through this access site, passed through the left orright iliac artery and the internal iliac artery, respectively, andplaced into either the left or right prostatic artery 96 (FIG. 12) forthe management and/or treatment of cancer associated with the prostate95 (FIG. 12).

Additional targets for the management/treatment of cancer associatedwith pelvic organs (e.g., urinary bladder, reproductive organs) includethe inferior mesenteric plexus (associated with the inferior mesentericartery), and the left colic plexus, sigmoid plexus, and superiorhemorrhoidal plexus (associated with branches of the inferior mesentericartery). Percutaneous intravascular access to these nerve structures caninclude passing a catheter through the left or right femoral artery(FIG. 14A), into the respective left or right common iliac artery 76(FIGS. 10 and 14A), into the abdominal aorta, and into the inferiormesenteric artery (not shown) and into the branches thereof, if desired.

In one embodiment, a breast cancer patient may be treated withneuromodulation of the internal mammary plexus, which is intimatelyassociated with the left and right internal thoracic arteries 33 (FIG.5), and which may be achieved through intravascular access. In aparticular example, and referring to FIGS. 5, 14A and 14B together, acatheter (not shown) may be inserted into the radial, brachial, oraxillary artery 38 and passed to the subclavian artery 33 and into theinternal thoracic artery 33 (FIG. 5). Alternatively, a catheter (notshown) may be inserted into the left or right femoral artery, passedthrough the left or right iliac artery to the abdominal aorta. From theabdominal aorta, the catheter can ascend the aorta to the aortic archwhere it can pass through the left or right subclavian arteries and intothe left or right internal thoracic arteries, respectively.

In other embodiments, neuromodulation of the pulmonary plexus, which isintimately associated with left and right pulmonary arteries 20, 21(FIG. 4) may be achieved through intravascular access. Referring to FIG.4 and back to FIGS. 14A and 14B, a treatment device (not shown), such asa catheter, may be inserted using standard angiographic technique intoeither the internal jugular, subclavian or femoral veins, and followingvenous inflow through the right atrium, tricuspid valve, rightventricle, pulmonic valve, and into the main pulmonary artery and rightand left pulmonary arteries thereafter to access a target treatment sitein the pulmonary vasculature that is in close proximity to thesympathetic chain.

B. Properties and Characteristics of the Vasculature

Properties and characteristics of the thoracic, abdominal and pelviccavity vasculature impose challenges to both access and treatmentmethods, and to system/device designs. Since neuromodulation of thevarious sympathetic nerve structures innervating the targeted thoracicorgans (e.g., pulmonary plexus, internal mammary plexus), the abdominalviscera (e.g., celiac plexus, superior mesenteric plexus, renal plexus,hepatic plexus, splenic plexus, gastric plexus, pancreatic plexus, etc.)or the pelvic/reproductive viscera (e.g., ovarian plexus, prostaticplexus, spermatic plexus, vaginal plexus, uterine plexus, sacral plexus,genitofemoral nerve, ilioinguinal nerve, pudendal nerve, perineal nerve,vesical plexus, hypogastric plexus, left colic plexus, sigmoid plexus,superior hemorrhoidal plexus, etc.) may be achieved in accordance withembodiments of the present technology through intravascular access,various aspects of the design of apparatus, systems, and methods forachieving such neuromodulation are disclosed herein. Aspects of thetechnology disclosed herein address additional challenges associatedwith variation of physiological conditions and architecture across thepatient population and/or within a specific patient across time, as wellas in response to cancer types and stage at diagnosis and/or treatment.For example, the design of the intravascular device and treatmentprotocols can address not only material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties, but also provideparticular algorithms and feedback protocols for delivering energy andobtaining real-time confirmatory results of successfully deliveringenergy to an intended target location in a patient-specific manner.

As discussed previously, a catheter may be advanced percutaneously intoeither the desired vasculature targets via a minimally invasiveintravascular path. However, minimally invasive arterial or venousaccess may be challenging for some targeted treatment sites, forexample, because as compared to some other larger arteries that areroutinely accessed using catheters, some of the target arteries (e.g.,internal thoracic arteries, testicular arteries, ovarian arteries,prostatic arteries, internal iliac artery, etc.) can be tortuous, may beof relatively small diameter, and/or may require adjustments to thelength and flexibility of the catheters. Arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, and/or length.Apparatus, systems and methods for achieving neuromodulation viaintravascular access can account for these and other aspects of arterialor venous anatomy and its variation across the patient population whenminimally invasively accessing an artery or vein. For example, spiral orhelical computed tomography (CT) technology can be used to produce 3Dimages of the vascular features for individual patients, andintravascular path choice as well as device size/diameter, length,flexibility, etc. can be selected based upon the patient's specificvascular features.

In addition to complicating arterial access, specifics of the thoracic,abdominal or pelvic anatomy also complicate establishment of stablecontact between neuromodulatory apparatus and a luminal surface or wallof an artery or vein. When the neuromodulatory apparatus includes anenergy delivery element, such as an electrode, transducer or acryotherapeutic device, consistent positioning and appropriate contactforce applied by the energy or cryotherapy delivery element to thevessel wall, and adhesion between the applicator and the vessel wall canbe important for predictability. However, navigation can be impeded bythe tight space within an artery, as well as tortuosity of the artery.Furthermore, establishing consistent contact can be complicated bypatient movement, respiration, and/or the cardiac cycle because thesefactors may cause significant movement of the artery relative to theaorta, for example, and the cardiac cycle may transiently distend thetarget artery (i.e., cause the wall of the artery to pulse). To addressthese challenges, the treatment device or applicator may be designedwith relative sizing and flexibility considerations. For example, theartery may have an internal diameter less than approximately 1.7 mm andthe treatment device can be delivered using a 3 French, or in somecases, a 4 French sized catheter. In a further example, the renal arterymay have an internal diameter in a range of about 2-10 mm and thetreatment device can be delivered using a 3, 4, 5, 6, 7 French, or insome cases, a 8 French sized catheter. To address challenges associatedwith patient and/or arterial movement during treatment, the treatmentdevice and neuromodulation system can be configured to use sensoryfeedback, such as impedance and temperature, to detect instability andto alert the operator to reposition the device and/or to temporarilystop treatment. In other embodiments, energy delivery algorithms can bevaried in real-time to account for changes detected due to patientand/or arterial movement. In further examples, the treatment device mayinclude one or more modifications or movement resistant enhancementssuch as atraumatic friction knobs or barbs on an outside surface of thedevice for resisting movement of the device relative to the desiredtissue location, positionable balloons for inflating and holding thedevice in a consistent and stable position during treatment, or thedevice can include a cryogenic component that can temporarily freeze oradhere the device to the desired tissue location.

After accessing a desired target artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventitia of the artery can be modulated viathe neuromodulatory apparatus. Effectively applying thermal treatmentfrom within an artery is non-trivial given the potential clinicalcomplications associated with such treatment. For example, the intimaand media of the artery are highly vulnerable to thermal injury. Asdiscussed in greater detail below, the intima-media thickness separatingthe vessel lumen from its adventitia means that target nerves may bemultiple millimeters distant (e.g., 2-3 mm) from the luminal surface ofthe artery. Sufficient energy can be delivered to or heat removed fromthe target sympathetic nerve fibers to modulate the target nerveswithout excessively cooling or heating the vessel wall to the extentthat the wall is frozen, desiccated, or otherwise potentially affectedto an undesirable extent. For example, when employing energy modalitiessuch as RF or ultrasound, energy delivery can be focused on a locationfurther from the interior vessel wall. In one embodiment, the majorityof the RF or ultrasound energy can be focused on a location (e.g., a“hot spot”) 2-3 mm beyond the interior surface of the vessel wall. Theenergy will dissipate from the hot spot in a radially decreasing manner.Thus, the targeted nerves can be modulated without damage to the luminalsurface of the vessel. A potential clinical complication associated withexcessive heating is thrombus formation from coagulating blood flowingthrough the artery. Given that this thrombus may cause irreversibledamage to the thoracic, abdominal or pelvic organ, thermal treatmentfrom within the artery can be applied carefully. Accordingly, thecomplex fluid mechanics and thermodynamic conditions present in theartery during treatment, particularly those that may impact heattransfer dynamics at the treatment site, may be important in applyingenergy (e.g., heating thermal energy) and/or removing heat from thetissue (e.g., cooling thermal conditions) from within the artery.Accordingly, sensory feedback, such as impedance and temperature, can beused to assess whether a desired energy distribution is administered atthe treatment site and can, in some instances, be used to change anenergy delivery algorithm in real-time to adjust for varyingfluctuations in the properties and conditions affecting heat transferdynamics at the treatment site.

The neuromodulatory apparatus can also be configured to allow foradjustable positioning and repositioning of a thermal energy deliveryelement (e.g., electrode, transducer, cryotherapeutic element or device,etc.) within the artery since location of treatment may also impactclinical efficacy. For example, full-circle lesion(s) likely resultingfrom a continuous circumferential treatment may be potentially relatedto artery stenosis. Therefore, the formation of more complex lesionsalong a longitudinal dimension of the artery via the cryotherapeuticdevices or other energy delivery elements (e.g., electrodes,transducers, etc.) and/or repositioning of the neuromodulatory apparatusto multiple treatment locations may be desirable. Additionally, variablepositioning and repositioning of the neuromodulatory apparatus may proveto be useful in circumstances where the artery is particularly tortuousor where there are proximal branch vessels off the artery main vessel,making treatment in certain locations challenging.

Blood flow through an artery may be temporarily occluded for a shorttime with minimal or no complications. However, occlusion for asignificant amount of time can be avoided in some cases to preventinjury to the organ such as ischemia. It can be beneficial to avoidocclusion altogether or, if occlusion is beneficial, to limit theduration of occlusion (e.g., 2-5 minutes).

C. Neuromodulation of Target Sympathetic Nerve at Treatment Site

Referring back to FIGS. 4-12, in some embodiments the shaft(s) 47, 65,66, 93 or 98, and the therapeutic element(s) 48, 68, 69, 94 or 99 can beportions of a treatment device at least partially corresponding to thetreatment device 102 shown in FIG. 13. Referring to FIGS. 4-13 together,the therapeutic element(s) 48, 68, 69, 94 99 or 120 (collectivelyreferred to as therapeutic element 120), for example, can be configuredto radially expand into a deployed state at the treatment location andto contact an inner wall of a vessel of the target vasculature for,e.g., causing a suitable lesion or pattern of lesions. During treatment,the therapeutic element 120 can be configured for partial or fullocclusion of a vessel. Partial occlusion can be useful, for example, toreduce ischemia, while full occlusion can be useful, for example, toreduce interference (e.g., warming or cooling) caused by blood flowthrough the treatment location. In some embodiments, the therapeuticelement 120 can be configured to cause therapeutically-effectiveneuromodulation (e.g., using ultrasound energy) without contacting avessel wall.

A variety of other suitable treatment locations are also possible in andaround the target artery, the target vein, and/or other suitablestructures. In a specific example, since the testicular artery 91 (FIG.11A) becomes narrower and more tortuous further from the aorta, it canbe more convenient in some cases to treat the testicular artery 91 atits trunk. Furthermore, a treatment procedure can include treatment atany suitable number of treatment locations, e.g., a single treatmentlocation, two treatment locations, or more than two treatment locations.In some embodiments, different treatment locations can correspond todifferent portions of the target artery, the target vein, and/or othersuitable structures proximate tissue having relatively highconcentrations of targeted sympathetic nerves (e.g., efferentsympathetic nerve fibers associated with organ comprising a malignanttumor, afferent nerve fibers associated with a diseased or damagedorgan). The shaft(s) 47, 65, 66, 93, 98 or 112 (collectively referred toas shaft 112) can be steerable (e.g., via one or more pull wires) andcan be configured to move the therapeutic element 120 between treatmentlocations. At each treatment location, the therapeutic element 120 canbe activated to cause modulation of nerves proximate the treatmentlocation. Activating the therapeutic element 120 can include, forexample, heating, cooling, stimulating, or applying another suitabletreatment modality at the treatment location. Activating the therapeuticelement 120 can further include applying various energy modalities atvarying power levels, intensities and for various durations forachieving modulation of nerves proximate the treatment location. In someembodiments, power levels, intensities and treatment duration can bedetermined and employed using various algorithms for ensuring modulationof nerves at select distances (e.g., depths) away from the treatmentlocation. Furthermore, as noted previously, in some embodiments, thetherapeutic element 120 can be configured to introduce (e.g., inject) achemical (e.g., a drug or other agent) into target tissue at thetreatment location. Such chemicals or agents can be applied at variousconcentrations depending on treatment location and the relative depth ofthe target nerves.

The therapeutic element 120 can be positioned at a treatment locationwithin the target artery, for example, via a catheterization pathincluding the femoral artery and the aorta (FIG. 14A), a catheterizationpath including the internal iliac artery, the external iliac artery orany vascular branches from these arteries, or another suitablecatheterization path, e.g., a radial or brachial catheterization path.Catheterization can be guided, for example, using imaging, e.g.,magnetic resonance, computed tomography, fluoroscopy, ultrasound,intravascular ultrasound, optical coherence tomography, or anothersuitable imaging modality. The therapeutic element 120 can be configuredto accommodate the anatomy of the target artery, the target vein, and/oranother suitable structure. For example, the therapeutic element 120 caninclude a balloon (not shown) configured to inflate to a size generallycorresponding to the internal size of the target artery, the targetvein, and/or another suitable structure. Other treatment procedures formodulation of sympathetic nerves in accordance with embodiments of thepresent technology are also possible.

FIG. 15 is a block diagram illustrating a method 1500 of modulatingsympathetic nerves using the system 100 described above with referenceto FIG. 13 or other suitable neuromodulation devices/systems. Withreference to FIGS. 4-13, and 15 together, the method 1500 can optionallyinclude determining the location of a primary malignant tumor in apatient (if not yet determined) and/or selecting a suitable patient forperforming neuromodulation (block 1502). For example, a suitable patientcan include a patient having cancer (e.g., a primary malignant tumor, ahematopoietic cancer), a patient at higher risk for developing cancer, apatient diagnosed with a pre-cancerous lesion and/or a patientpreviously treated for cancer. The method 1500 can includeintravascularly locating the neuromodulation assembly 120 in a deliverystate (e.g., low-profile configuration) at a first target site in ornear a target blood vessel such as those listed in TABLES 1-3 and/orthose having close proximity to a target SNS nerve fiber in the body(e.g., a pulmonary artery or vein, an internal thoracic artery, a celiacartery, superior mesenteric artery or vein, a renal artery or vein, ahepatic artery, a splenic artery or vein, a gastric artery, an inferiormesenteric artery or vein, a pancreatic artery, an ovarian artery orvein, a vaginal artery or vein, a uterine artery or vein, a testicularartery or vein, a prostatic artery, a common iliac artery or vein, aninternal iliac artery or vein, an external iliac artery or vein, aninternal pudendal artery or vein, a superior gluteal artery or vein,deep circumflex iliac artery or vein and/or another suitable structure)(block 1505).

In accordance with aspects of the present technology, a patient can betreated at one or more than one target sites. In certain embodiments,for example, a target site is adjacent to a target sympathetic nerveinnervating tissue proximate the primary malignant tumor in the patient.Targeting SNS nerves innervating tissue or organs comprising cancercells is expected to result in reduced or lower SNS nerve activity insuch tissues, thereby inhibiting, preventing, slowing, disrupting orreversing tumor progression and/or metastasis of the primary cancer inthe patient. In another embodiment, the target site is adjacent a renalnerve of the patient. Targeting the renal nerve for neuromodulation isanticipated to reduce renal norepinephrine spillover, whole bodynorepinephrine spillover, and reduce central sympathetic drive (e.g.,reduce a level of efferent SNS nerve firing) in the patient, therebyinhibiting, preventing, slowing, disrupting or reversing tumorprogression and/or metastasis of the primary cancer in the patient. In afurther embodiment, the target site is adjacent a target sympatheticnerve innervating a secondary tissue location, wherein the secondarytissue location has an increased likelihood of developing a metastatictumor (e.g., based on the type/location of the primary malignant tumor).Without being bound by theory, targeting secondary tissue location(s) isanticipated to decrease a rate of colonization of circulating tumorcells at the secondary tissue site by, for example, altering amicroenvironment at the secondary tissue location to be less habitableto colonization by the circulating tumor cells.

When intravascularly locating the neuromodulation assembly 120, thetreatment device 102 and/or portions thereof (e.g., the neuromodulationassembly 120) can be inserted into a guide catheter or sheath tofacilitate intravascular delivery of the neuromodulation assembly 120.In certain embodiments, for example, the treatment device 102 can beconfigured to fit within an 8 Fr guide catheter or smaller (e.g., 7 Fr,6 Fr, 5 Fr, 4 Fr, 3 Fr, etc.) to access small peripheral vessels. Aguide wire (not shown), if present, can be used to manipulate andenhance control of the shaft 112 and the neuromodulation assembly 120(e.g., in an over-the-wire or a rapid-exchange configuration). In someembodiments, radiopaque markers and/or markings on the treatment device102 and/or the guide wire can facilitate placement of theneuromodulation assembly 120 at the target site (e.g., a target vesselof a patient with cancer). In some embodiments, a contrast material canbe delivered distally beyond the neuromodulation assembly 120, andfluoroscopy and/or other suitable imaging techniques can be used to aidin placement of the neuromodulation assembly 120 at the target site.

The method 1500 can further include connecting the treatment device 102to the console 130 (block 1510), and determining whether theneuromodulation assembly 120 is in the correct position at the targetsite and/or whether the neuromodulation assembly (e.g., electrodes orcryotherapy balloon) is functioning properly (block 1515). After theneuromodulation assembly 120 is adequately positioned in the targetvessel, it can be radially expanded or otherwise deployed using thehandle 116 or other suitable control mechanism until the neuromodulationassembly 120 is positioned at its target site and in stable contact withthe inner wall of the target vessel.

Once the neuromodulation assembly 120 is properly located at the targetsite and no malfunctions are detected, the console 130 can bemanipulated to initiate application of an energy field provided by theenergy source 104 to the target site to cause electrically-inducedand/or thermally-induced modulation of target sympathetic nerves nearthe target vessel (e.g., using electrodes or cryotherapeutic devices)(block 1520). The purposeful application of energy from theneuromodulation assembly 120 is applied to tissue to induce one or moredesired neuromodulating effects on localized regions of the targetvessel and adjacent regions of the target sympathetic nerve fibers,which lay intimately within, adjacent to, or in close proximity to theadventitia of the target vessel. The neuromodulating effects may includedenervation, thermal ablation, and non-ablative thermal alteration ordamage (e.g., via sustained heating and/or resistive heating). Thepurposeful application of the energy may achieve neuromodulation alongall or at least a portion of the target sympathetic nerve fibers.

In the deployed state, the neuromodulation assembly 120 can, in oneembodiment, be configured to contact an inner wall of a target vessel toform a suitable lesion or pattern of lesions without the need forrepositioning. For example, the neuromodulation assembly 120 can beconfigured to form a single lesion or a series of lesions, e.g.,overlapping and/or non-overlapping. In some embodiments, the lesion(s)(e.g., pattern of lesions) can extend around generally the entirecircumference of the vessel, but can still be non-circumferential atlongitudinal segments or zones along a lengthwise portion of the vessel.This can facilitate precise and efficient treatment with a lowpossibility of vessel stenosis. In other embodiments, theneuromodulation assembly 120 can be configured to form apartially-circumferential lesion or a fully-circumferential lesion at asingle longitudinal segment or zone of the vessel.

Accordingly, heating and/or cooling of the neuromodulation assembly 120causes modulation of sympathetic nerves (e.g., efferent SNS fibersreleasing catecholamines at innervated tissue sites, afferent nervefibers transmitting sensory and pain signals that increase centralsympathetic drive) at the target site to attenuate neural traffic alongthe target sympathetic nerves to provide a therapeutic beneficialreduction in one or more physiological parameters corresponding to theprogression of the cancer in the patient.

In one example, the treatment device 102 can be an RF energy emittingdevice and RF energy can be delivered through energy delivery elementsor electrodes to one or more locations along the inner wall of thetarget vessel for predetermined periods of time (e.g., 120 seconds). Insome embodiments, multiple treatments (e.g., 4-6) may be administered inmultiple target vessel locations as discussed above to achieve a desiredcoverage and/or desired inhibition of sympathetic neural activity in thebody. For example, the target vessel can be a first target vessel (e.g.,a first testicular artery) and the treatment procedure can includemodulating nerves associated with a second target vessel (e.g., a secondtesticular artery) for the treatment of cancer associated with thetestes. In another example, treatment for a patient diagnosed withpancreatic cancer can include modulating nerves (e.g., celiac plexus)associated with a first target vessel (e.g., a celiac artery) and caninclude modulating nerves (e.g., superior mesenteric plexus) associatedwith a second target vessel (e.g., a superior mesenteric artery). In yetanother example, treatment for a patient diagnosed with a primarymalignant tumor can include modulating nerves innervating tissueproximate the primary malignant tumor and associated with a first targetvessel, and can include modulating nerves (e.g., renal plexus)associated a second target vessel (e.g., renal artery) for reducing,e.g., a level of whole body norepinephrine spillover. In a furtherembodiment, the treatment for a patient diagnosed with the primarymalignant tumor can also include modulating nerves innervating a likelymetastatic tissue location (e.g., liver, lung, etc.) and associated witha third target vessel for decreasing, e.g., a rate of colonization ofcirculating tumor cells at the likely metastatic tissue location.

In some embodiments, a treatment procedure can include applying asuitable treatment modality at a treatment location in a testing stepfollowed by a treatment step. The testing step, for example, can includeapplying the treatment modality at a lower intensity and/or for ashorter duration than during the treatment step. This can allow anoperator to determine (e.g., by neural activity sensors and/or patientfeedback) whether nerves proximate the treatment location are suitablefor modulation. Performing a testing step can be particularly useful fortreatment procedures in which targeted nerves are closely associatedwith nerves that could cause undesirable side effects if modulatedduring a subsequent treatment step.

A technical objective of a treatment may be, for example, to heat tissueto a desired depth (e.g., at least about 3 mm) to a temperature thatwould ablate nerve tissue (e.g., about 65° C.). A clinical objective ofthe procedure typically is to neuromodulate (e.g., lesion) a sufficientnumber of sympathetic nerves (either efferent or afferent nerves) tocause a reduction in sympathetic tone or drive to the organ(s). If thetechnical objective of a treatment is met (e.g., tissue is heated toabout 65° C. to a depth of about 3 mm) the probability of forming alesion in nerve tissue is high. The greater the number of technicallysuccessful treatments, the greater the probability of modulating asufficient proportion of nerves, and thus the greater the probability ofclinical success.

In a specific example of using RF energy for sympathetic nervemodulation, a clinician can commence treatment, which causes the controlalgorithm 134 (FIG. 13) to initiate instructions to the generator (notshown) to gradually adjust its power output to a first power level(e.g., 5 watts) over a first time period (e.g., 15 seconds). The powerincrease during the first time period is generally linear. As a result,the generator increases its power output at a generally constant rate ofpower/time. Alternatively, the power increase may be non-linear (e.g.,exponential or parabolic) with a variable rate of increase. Once thefirst power level and the first time are achieved, the algorithm mayhold at the first power level until a second predetermined period oftime has elapsed (e.g., 3 seconds). At the conclusion of the secondperiod of time, power is again increased by a predetermined increment(e.g., 1 watt) to a second power level over a third predetermined periodof time (e.g., 1 second). This power ramp in predetermined increments ofabout 1 watt over predetermined periods of time may continue until amaximum power P_(MAX) is achieved or some other condition is satisfied.In one embodiment, P_(MAX) is 8 watts. In another embodiment P_(MAX) is10 watts. Optionally, the power may be maintained at the maximum powerP_(MAX) for a desired period of time or up to the desired totaltreatment time (e.g., up to about 120 seconds).

In another specific example, the treatment device 102 can be a cryogenicdevice and cryogenic cooling can be applied for one or more cycles(e.g., for 30 second increments, 60 second increments, 90 secondincrements, etc.) in one or more locations along the circumferenceand/or length of the target vessel. The cooling cycles can be, forexample, fixed periods or can be fully or partially dependent ondetected temperatures (e.g., temperatures detected by a thermocouple(not shown) of the neuromodulation assembly 120). In some embodiments, afirst stage can include cooling tissue until a first target temperatureis reached. A second stage can include maintaining cooling for a setperiod, such as 15-180 seconds (e.g., 90 seconds). A third stage caninclude terminating or decreasing cooling to allow the tissue to warm toa second target temperature higher than the first target temperature. Afourth stage can include continuing to allow the tissue to warm for aset period, such as 10-120 seconds (e.g., 60 seconds). A fifth stage caninclude cooling the tissue until the first target temperature (or adifferent target temperature) is reached. A sixth stage can includemaintaining cooling for a set period, such as 15-180 seconds (e.g., 90seconds). A seventh stage can, for example, include allowing the tissueto warm completely (e.g., to reach a body temperature).

After providing the therapeutically-effective neuromodulation energy(e.g., cryogenic cooling, RF energy, ultrasound energy, etc.), themethod 1500 may also include removing the treatment device 102 (e.g.,catheter) and the neuromodulation assembly 120 from the patient (block1525). In some embodiments, the neuromodulation assembly 120 can be animplantable device and a treatment procedure can include locating theneuromodulation assembly 120 at the treatment location using the shaft112, fixing the neuromodulation assembly 120 at the treatment location,separating the neuromodulation assembly 120 from the shaft 112, andwithdrawing the shaft 112. Other treatment procedures for modulation oftarget sympathetic nerves in accordance with embodiments of the presenttechnology are also possible.

The method 1500 may further include determining whether theneuromodulation therapeutically treated the cancer patient or otherwisesufficiently modulated nerves or other neural structures proximate thetarget site(s) for inhibiting, preventing, slowing, disrupting orreversing tumor progression and/or metastasis of the primary cancer inthe patient (block 1530). For example, the process of determiningwhether the neuromodulation therapeutically treated the nerves caninclude determining whether nerves were sufficiently modulated orotherwise disrupted to reduce, suppress, inhibit, block or otherwiseaffect the afferent and/or efferent signals, such as norepinephrinerelease by terminal nerve fibers (e.g., by evaluation of suitablebiomarkers, stimulation and recording of nerve signals, etc.). In afurther embodiment, patient assessment could be performed at timeintervals (e.g., 1 month, 3 months, 6 months, 12 months, etc.) followingneuromodulation treatment. For example, the patient can be assessed formeasures of sympathetic activity (e.g., MSNA, and/or norepinephrinespillover to plasma, whole body norepinephrine spillover, and heart ratevariability), measures of localized inflammation (e.g., IL-6, IL-8,etc.), and measures of cancer progression (e.g., tumor growth, cancerspread, etc.).

In other embodiments, various steps in the method 1500 can be modified,omitted, and/or additional steps may be added. In further embodiments,the method 1500 can have a delay between applyingtherapeutically-effective neuromodulation energy to a first target siteat or near a first target vessel and applying therapeutically-effectiveneuromodulation energy to a second target site at or near a secondtarget vessel. For example, neuromodulation treatment of nervesinnervating tissue proximate the primary malignant tumor and associatedwith a first target vessel can take place at a first treatment session,and neuromodulation at the renal artery can take place a secondtreatment session at a later time.

As discussed previously, treatment procedures for modulation ofsympathetic nerves in accordance with embodiments of the presenttechnology are expected to improve one or more parameters associatedwith cancer progression (e.g., tumor growth, tumor vascularization,tumor metastasis, etc.). These and other clinical effects are expectedto be detectable immediately after a treatment procedure or after adelay, e.g., of 1, 2, or 3 months. In some cases, sympathetic nerves canregenerate to a greater degree than other nerves. Accordingly, it may beuseful to repeat neuromodulation at the same treatment location or adifferent treatment location after a suitable delay, e.g., 1, 2, or 3years. In still other embodiments, however, other suitable treatmentregimens or techniques may be used.

VII. EXPERIMENTAL EXAMPLES Example 1

This section describes an example of the outcome of renalneuromodulation on human patients. A total of 45 patients (mean age of58±9 years) diagnosed with essential hypertension were treated withpercutaneous, catheter based renal nerve ablation. Treatment included RFenergy delivery to the renal artery using a single-electrode SymplicityFlex™ catheter commercially available from Medtronic, Inc., of 710Medtronic Parkway, Minneapolis, Minn. 55432-5604. In this human trial, aradiotracer dilution method was used to assess overflow ofnorepinephrine from the kidneys into circulation before and 15-30 daysafter the procedure in 10 patients. Bilateral renal-nerve ablationresulted in a marked reduction in mean norepinephrine spillover fromboth kidneys: 47% (95% confidence interval) one month after treatment.

In a similar human trial where bilateral renal nerve ablation wasperformed in 70 patients, whole-body norepinephrine levels (i.e., ameasure of “total” sympathetic activity), fell by nearly 50% after renalnerve ablation and measurement of muscle sympathetic nerve activityshowed a drop of 66% over 6 months, further supporting the conclusionthat total sympathetic dive was reduced by the renal denervationprocedure in this patient group.

Example 2

Example 2 describes the outcome of catheter-based renal neuromodulationon animal subjects in an additional experiment. In this example (andreferring to FIGS. 16A and 16B), studies using the pig model wereperformed using a multi-electrode Symplicity Spyral™ catheter or asingle-electrode Symplicity Flex™ catheter along with a Symplicity G3™generator. The catheters and generator are commercially available fromMedtronic, Inc., of 710 Medtronic Parkway, Minneapolis, Minn.55432-5604. The catheters were used in these cohorts of animals (n=66)to create multiple RF ablations in the renal vasculature. Cortical axondensity in the renal cortex (FIG. 16A) and renal cortical norepinephrine(NE) concentration (FIG. 16B) were used as markers to measure proceduralefficacy.

As shown in FIG. 16A, cortical axon area (per mm²) dropped approximatelygreater than 54% between a control group (n=64) and treated groups ofpigs (n=66) undergoing treatment. For pigs undergoing treatment with theSymplicity Flex™ catheter (n=54), an average of 4.1 lesions were formedin each animal. These pigs demonstrated a 56.9% increase innon-functional axonal area along the renal artery, and a 68% decrease incortical axon area as compared with the control group. For pigsundergoing treatment with the Symplicity Spyral™ catheter (n=12), anaverage of 4.0 lesions were formed in each animal. The pigs undergoingtreatment with the Symplicity Spyral™ catheter demonstrated a 47.3%increase in non-functional area along the renal artery, and a 54%decrease in cortical axon area relative to the control group. Withoutbeing bound by theory, it is believed that the loss of cortical axons isa likely consequence of nerve atrophy distal to the ablation sites.

FIG. 16B includes (a) a graph of normalized cortical axon area vs. renalNE concentration, and (b) a graph of renal NE concentration vs. extent(%) of nerve ablation. Referring to the table of FIG. 16A and the twographs of FIG. 16B together, cortical axon area correlates directly withrenal NE. In particular, pigs undergoing treatment with the SymplicityFlex™ catheter exhibited a 65% decrease in mean NE level compared withthe pigs in the control group. The pigs treated with the SymplicitySpyral™ catheter exhibited a 68% decrease in mean NE level compared withthe pigs in the control group. This is further shown by the first graphof FIG. 16B, which demonstrates that a decrease in cortical axon areacorrelates with a decrease in NE levels. Referring to the second graphof FIG. 16B, renal NE decrease is non-linear with increased loss ofnerve viability along the artery (further extent (%) of nerve ablation).These findings suggest that catheter-based renal neuromodulationexhibits a relatively consistent impact on sympathetic nerve functionand viability, and further suggest that neuromodulation of SNS fibersinnervating a target tissue and/or organ (such as the kidney) result ina significant decrease in local NE concentration.

Example 3

Example 3 describes a method for treating human patients with renalneuromodulation and anticipated outcomes of such treatment. In thisexample, human patients diagnosed with cancer will be treated with renaldenervation and a method of treatment includes modulating nerve tissuesurrounding the main renal artery (e.g., locations along the main renalvessel, locations at or near the bifurcation, etc.) and/or modulatingnerve tissue surrounding one or more primary branch trunks (e.g.,proximal portion of one or more primary branch vessels distal to thebifurcation).

For patients undergoing distal main renal artery treatment, modulatingnerve tissue includes forming up to about six lesions at the distalsegment of the renal artery and within a distance of approximately 6 mmproximal to the branch point within the renal artery using theSymplicity Flex™ catheter. The longitudinal spacing between the lesionsmay be approximately 2 mm, with a lesion footprint of approximately 2 mmeach. For example, a first lesion can be formed about 5-6 mm from thebifurcation. The catheter can then be proximally retracted 1-2 mm androtated 90 degrees followed by formation of a second lesion. Furtherlesions can be formed by sequential movement of the catheter proximally1-2 mm, rotation of 90 degrees followed by lesion formation. As such, alongitudinal separation of lesions can occur approximately 1-2 mm apartalong the longitudinal length of the distal segment of the main renalartery. For patients undergoing main artery treatment at a centralsegment of the main renal artery, a Symplicity Flex™ catheter can beused to form between 4 and 6 ablations in a spiral/helical pattern alongthe central segment of the main renal artery. For example, the firstlesion can be placed approximately 5 mm proximal to the bifurcation,with each subsequent lesion placed 5 mm proximally with 90 degreerotation to form a spiral/helical pattern.

For patients undergoing renal branch treatment, modulating nerve tissueincludes forming up to about four lesions (e.g., about 2 lesions toabout 4 lesions) in one or more primary branch trunks (e.g., from about1 mm to about 6 mm distal to the primary bifurcation, in regions greaterthan 2 mm distal to the primary bifurcation). Modulation of nerve tissueat branch trunk treatment sites and/or different combinations oftreatment sites within the renal vasculature (e.g., locations along themain renal vessel, locations at or near the bifurcation, etc.) can beperformed using a single-electrode Symplicity Flex™ catheter or amulti-electrode Symplicity Spyral™ catheter, both commercially availablefrom Medtronic, Inc. Other multi-electrode, spiral/helical-shapedcatheters having a tighter spiral/helix (e.g., smaller pitch) forforming multiple lesions close in proximity along the length of thevessel are contemplated for these methods. In a particular example, amethod for efficaciously neuromodulating renal nerve tissue in a humanpatient can include advancing a single-electrode Symplicity Flex™catheter to a first renal artery branch vessel approximately 6 mm distalto the bifurcation. A first lesion can be formed about 5-6 mm distal tothe bifurcation. The catheter can then be proximally retracted 1-2 mm(e.g., maximum of 2 mm) and rotated 90 degrees followed by formation ofa second lesion. Further lesions can be formed by sequential movement ofthe catheter proximally 1-2 mm, rotation of 90 degrees followed bylesion formation. As such, a longitudinal separation of lesions canoccur approximately 1-2 mm apart along the longitudinal length of thefirst renal artery branch vessel (e.g., first branch trunk). In otherexamples, the catheter can be rotated (e.g., 90 degrees) followingformation of the first lesion such that discrete lesions (e.g.,non-continuous) are formed in the same longitudinal plane. Followingtreatment at the first renal artery branch, the catheter can bewithdrawn into the main renal vessel and then advanced under fluoroscopyinto a second renal artery branch and the treatment procedure can berepeated. Some methods can include treating two branch vessels at theproximal trunk segment of the branch vessel. Other methods can includetreating greater than two or all of the primary branch vessels branchingfrom the main renal vessel (e.g., distal to a primary bifurcation). Asdescribed above, these methods may also include combiningneuromodulation of renal nerve tissue surrounding one or more primarybranch trunks with neuromodulation of renal nerve tissue at additionaltreatment location (e.g., locations along the main renal vessel,locations at or near the bifurcation, etc.). Other methods can includeadvancing a single-electrode Symplicity Flex™ catheter to a first renalartery branch vessel approximately 10 mm distal to the bifurcation. Thefirst lesion can be formed about 9-10 mm distal to the bifurcation, andthe catheter can then be proximally retracted and rotated for formingsubsequent lesions as discussed above.

Physiological biomarkers, such as systemic catecholamines and/or theirsubsequent degradation products could be measured in either plasma,serum or urine to serve as surrogate markers to measure proceduralefficacy such as described in International Patent Application No.PCT/US2015/047568, filed Aug. 28, 2015, and incorporated herein byreference in its entirety.

It is anticipated that treating a human patient diagnosed with cancer(e.g., primary malignant tumor at various locations in the body,hematopoietic cancer, etc.), pre-cancer, or a higher risk of cancer,with renal neuromodulation, at one or more of the described treatmentlocations, will inhibit sympathetic neural activity in the renal nervein a manner that reduces a central sympathetic drive (e.g., ascorrelated with whole body norepinephrine spillover and/or renalnorepinephrine spillover) by greater than about 20%, about 30%, about40%, about 50% or greater than about 60% in about 1 month, in about 3months, in about 6 months or in about 12 months, or in anotherembodiment, in about 3 months to about 12 months, after renalneuromodulation treatment. Reduction in central sympathetic drive isanticipated to result in a therapeutically beneficial reduction in oneor more measurable physiological parameters corresponding to theprogression, initiation, and/or reoccurrence of cancer in the patient.

Example 4

Example 4 describes a method for treating human patients diagnosed withbreast cancer with targeted sympathetic neuromodulation of SNS neuralfibers innervating breast parenchyma and anticipated outcomes of suchtreatment. In this example, human patients diagnosed with a primarymalignant tumor in the breast will be treated with neuromodulation ofthe internal mammary plexus which includes modulating SNS nerve tissuesurrounding the internal thoracic artery.

For patients diagnosed with breast cancer, treatment can includetargeting SNS neural fibers innervating the affected breast tissue(e.g., left or right breast), or in other embodiments, the method caninclude treating breast tissue associated with both breasts. Modulatingnerve tissue can include forming up to about six lesions along a segmentof the left and/or right internal thoracic arteries (e.g., afterbranching from the left and/or right subclavian arteries, respectively)using the single-electrode Symplicity Flex™ catheter or themulti-electrode Symplicity Spyral™ catheter, both commercially availablefrom Medtronic, Inc. The longitudinal spacing between the lesions may beapproximately 2 mm-5 mm, with a lesion footprint of approximately 2 mmeach. When using the Symplicity Flex™ catheter, for example, followingformation of a first lesion at a distalmost portion of the targetedinternal thoracic artery, the catheter can then be proximally retracted1-2 mm or 2-5 mm and rotated 90 degrees followed by formation of asecond lesion. Further lesions can be formed by sequential movement ofthe catheter proximally 1-2 mm or 2-5 mm, rotation of 90 degreesfollowed by lesion formation. As such, a longitudinal separation oflesions can occur approximately 1-2 mm apart along the longitudinallength of the targeted segment of the internal thoracic artery.Following treatment at the first internal thoracic artery, the cathetercan be withdrawn into the arch of the aorta and then advanced underfluoroscopy through the subclavian artery and into a second internalthoracic artery (e.g., on the contralateral side from the first selectedtreatment location) and the treatment procedure can be repeated.

Procedural efficacy may be measured using, for example, radiotracerdilution techniques that allow the estimation of regional sympatheticnervous activity from measurements of the organ-specific norepinephrinespillover rate. In an additional example, norepinephrine levels inbreast tissue may be measured from biopsies taken at baseline (e.g.,prior to breast SNS neuromodulation) and after treatment (e.g., about 1month, 2 months, 3 months, 6 months, 12 months or more after treatment).Whole body physiological biomarkers, such as systemic catecholaminesand/or their subsequent degradation products could be measured in eitherplasma, serum or urine to serve as surrogate markers to measureprocedural efficacy such as described in International PatentApplication No. PCT/US2015/047568, filed Aug. 28, 2015, and incorporatedherein by reference in its entirety.

It is anticipated that treating a human patient diagnosed with breastcancer (e.g., primary malignant tumor), a pre-cancer lesion or conditionin the breast tissue, or a higher risk of developing breast cancer, withtargeted neuromodulation of SNS nerve fibers associated with theinternal thoracic artery will inhibit sympathetic neural activity in theinternal mammary plexus in a manner that reduces a local sympatheticdrive to the breast parenchyma by greater than about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70% or greater thanabout 80% in about 1 month, in about 3 months, in about 6 months or inabout 12 months, or in another embodiment, in about 3 months to about 12months, after neuromodulation treatment. Reduction in localizedsympathetic drive to breast tissue in breast cancer patients isanticipated to result in a therapeutically beneficial reduction in oneor more measurable physiological parameters corresponding to theprogression, initiation, and/or reoccurrence of breast cancer in thepatient.

It is further anticipated that neuromodulation treatments directed attarget sympathetic nerves innervating organs and/or other tissuescomprising or proximate to a primary source of cancer cells, including aprimary malignant tumor, can be therapeutically beneficial for one ormore of reducing a tumor growth rate and/or a rate of cancer celldivision, decreasing a frequency of metastasis of the primary cancer, atleast partially inhibiting vascularization of a primary malignant tumorat the targeted site, decreasing a number of metastatic tumors derivedfrom the primary malignant tumor in the patient, and/or increasingeffectiveness of chemotherapy drugs on the cancer cells within theprimary malignant tumor. It is further anticipated that neuromodulationtreatments directed at target sympathetic nerves innervating organs ortissue structures having a high likelihood of developing a metastatictumor from circulating cancer cells can beneficially decrease a rate ofcolonization of circulating tumor cells at those targeted sites.

VIII. FURTHER EXAMPLES

1. A method of treating a human patient diagnosed with a primarymalignant tumor, the method comprising:

-   -   intravascularly positioning a catheter carrying a        neuromodulation assembly adjacent to a target sympathetic nerve        innervating tissue proximate the primary malignant tumor in the        patient;    -   delivering energy to the target sympathetic nerve via the        neuromodulation assembly to attenuate neural traffic along the        target sympathetic nerve; and    -   removing the catheter and neuromodulation assembly from the        patient after treatment,    -   wherein attenuating neural traffic along the target sympathetic        nerve results in one or more of—        -   a reduction in a tumor growth rate of the primary malignant            tumor in the patient;        -   a decrease in a frequency of metastasis of the primary            malignant tumor;        -   at least partial inhibition of vascularization of the            primary malignant tumor;        -   a decrease in a number of metastatic tumors derived from the            primary malignant tumor in the patient; and        -   increased effectiveness of a chemotherapy agent on cancer            cells derived from the primary malignant tumor.

2. The method of example 1 wherein attenuating neural traffic along thetarget sympathetic nerve further decreases a number of circulating tumorcells in the patient.

3. The method of example 1 or example 2 wherein attenuating neuraltraffic along the target sympathetic nerve further inhibits at least oneof lymphatic spread or hematogenous spread of tumor cells from theprimary malignant tumor in the patient.

4. The method of any one of examples 1-3 wherein the primary malignanttumor is located in the breast, colon, kidney, pancreas, liver,prostate, cervix or ovary of the patient.

5. The method of example 1, further comprising:

-   -   intravascularly positioning a second neuromodulation assembly        adjacent to a renal nerve of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the second neuromodulation        assembly,    -   wherein inhibiting sympathetic neural activity in the renal        nerve improves a measurable physiological parameter        corresponding to the primary malignant tumor of the patient.

6. The method of example 5 wherein reducing sympathetic neural activityin the renal nerve in a manner that improves a measurable physiologicalparameter corresponding to the primary malignant tumor comprisesreducing at least one of a primary malignant tumor growth rate, aprimary malignant tumor size, a degree of vascularization of a primarymalignant tumor and a number of circulating tumor cells.

7. The method of example 5 or example 6 wherein reducing sympatheticneural activity in the renal nerve in a manner that improves ameasurable physiological parameter corresponding to the primarymalignant tumor comprises improving an effectiveness of a chemotherapyagent on tumor cells in the patient.

8. The method of any one of examples 5-7 wherein reducing sympatheticneural activity in the renal nerve further reduces muscle sympatheticnerve activity (MSNA) in the patient.

9. The method of any one of examples 5-8 wherein reducing sympatheticneural activity in the renal nerve further reduces whole bodynorepinephrine spillover in the patient.

10. The method of example 9 wherein the whole body norepinephrinespillover is reduced by at least about 20% in about one month afterreducing sympathetic neural activity in the renal nerve.

11. The method of example 9 or example 10 wherein the whole bodynorepinephrine spillover is reduced by greater than about 40% in aboutthree months to about 12 months after reducing sympathetic neuralactivity in the renal nerve.

12. The method of any one of examples 9-11 wherein reducing whole bodynorepinephrine spillover in the patient decreases a level ofvasoconstriction of vessels vascularizing tissue at or near the primarymalignant tumor.

13. The method of any one of examples 9-12 wherein reducing whole bodynorepinephrine spillover in the patient decreases a number of coloniesformed by circulating tumor cells at secondary tissue sites.

14. The method of any one of examples 9-13 wherein reducing whole bodynorepinephrine spillover in the patient decreases a rate of colonizationof circulating tumor cells at secondary tissue sites.

15. The method of example 13 or example 14 wherein the secondary tissuesites are at least one of bone, lungs, liver and brain.

16. The method of example 1 or example 5, further comprising:

-   -   intravascularly positioning a third neuromodulation assembly        adjacent to a second target sympathetic nerve innervating a        secondary tissue site; and    -   delivering energy to the second target sympathetic nerve via the        third neuromodulation assembly to attenuate neural traffic along        the second target sympathetic nerve,    -   wherein attenuating neural traffic along the second target        sympathetic nerve decreases a rate of colonization of        circulating tumor cells at the secondary tissue site.

17. The method of example 16 wherein the secondary tissue site is theliver, and wherein the third neuromodulation assembly is positionedwithin the celiac artery or the hepatic artery of the patient.

18. The method of example 16 wherein the secondary tissue site is thelung, and wherein the third neuromodulation assembly is positionedwithin a pulmonary artery of the patient.

19. The method of any one of examples 1-18 wherein attenuating neuraltraffic along the target sympathetic nerve comprises at least partiallyablating the target sympathetic nerve.

20. The method of any one of examples 1-18 wherein attenuating neuraltraffic along the target sympathetic nerve comprises reducingsympathetic neural activity in the tissue proximate the primarymalignant tumor in the patient.

21. The method of any one of examples 1-18 wherein attenuating neuraltraffic along the target sympathetic nerve comprises at least partiallydisrupting communication along sympathetic neural fibers.

22. The method of any one of examples 1-18 wherein attenuating neuraltraffic along the target sympathetic nerve comprises irreversiblydisrupting communication along sympathetic neural fibers.

23. The method of any one of examples 1 and 19-22 wherein saidattenuating neural traffic along the target sympathetic nerve isirreversible.

24. The method of any one of examples 1 and 19-22 wherein saidattenuating neural traffic along the target sympathetic nerve istemporary.

25. The method of any one of examples 1-24 wherein attenuating neuraltraffic along the target sympathetic nerve comprises delivering anenergy field to the target sympathetic nerve via the neuromodulationassembly.

26. The method of example 25 wherein delivering an energy field to thetarget sympathetic nerve comprises delivering at least one of radiofrequency energy, ultrasound energy, high intensity ultrasound energy,laser energy, and microwave energy via the neuromodulation assembly.

27. A method of treating a human patient diagnosed with cancer, themethod comprising:

-   -   intravascularly positioning a neuromodulation assembly adjacent        to a renal nerve of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the neuromodulation assembly,    -   wherein at least partially inhibiting sympathetic neural        activity results in a therapeutically beneficial reduction in        one or more measurable physiological parameters corresponding to        the progression of the cancer in the patient.

28. The method of example 27 wherein a measurable physiologicalparameter corresponding to the progression of the cancer is at least oneof a primary malignant tumor growth rate, a primary malignant tumorsize, a degree of vascularization of a primary malignant tumor and anumber of circulating tumor cells.

29. The method of example 27 or example 28 wherein at least partiallyinhibiting sympathetic neural activity in the renal artery in a mannerthat results in a therapeutically beneficial reduction in one or moremeasurable physiological parameters comprises reducing at least one ofan amount of lymphatic spread or hematogenous spread of tumor cells froma primary malignant tumor in the patient.

30. The method of any one of examples 27-29 wherein at least partiallyinhibiting sympathetic neural activity in the renal artery in a mannerthat results in a therapeutically beneficial reduction in one or moremeasurable physiological parameters comprises reducing a number oftumor-associated macrophages within or in proximity to a primarymalignant tumor in the patient.

31. The method of any one of examples 27-30 wherein at least partiallyinhibiting sympathetic neural activity in the renal nerve furtherreduces whole body norepinephrine spillover in the patient.

32. The method of example 31 wherein the whole body norepinephrinespillover is reduced by at least about 20% in about one month after atleast partially inhibiting sympathetic neural activity in the renalnerve.

33. The method of example 31 or example 32 wherein the whole bodynorepinephrine spillover is reduced by greater than about 40% in aboutthree months to about 12 months after at least partially inhibitingsympathetic neural activity in the renal nerve.

34. The method of any one of examples 27-33 wherein the patient isdiagnosed with a primary malignant tumor, and wherein at least partiallyinhibiting sympathetic neural activity further reduces whole bodynorepinephrine spillover in the patient in a manner that decreases afrequency of metastasis of the primary malignant tumor.

35. The method of example 34 wherein the primary malignant tumor is inone of the breast, pancreas, lung, prostate, ovary, colon, liver, kidneyand skin.

36. The method of example 27 wherein the patient is diagnosed withlymphoma or leukemia.

37. The method of any one of examples 27-36 wherein the neuromodulationassembly is carried by a catheter, and wherein the method furthercomprises removing the catheter and the neuromodulation assembly fromthe patient after treatment.

38. The method of any one of examples 27-37 wherein at least partiallyinhibiting sympathetic neural activity in the renal nerve of the patientcomprises at least partially ablating the renal nerve.

39. The method of any one of examples 27-38 wherein at least partiallyinhibiting sympathetic neural activity in the renal nerve of the patientcomprises irreversibly disrupting communication along at least somesympathetic neural fibers.

40. The method of example 27, further comprising:

-   -   percutaneously introducing an energy delivery element at a        distal portion of a catheter proximate to neural fibers that        control a function of an organ comprising a primary malignant        tumor in the patient;    -   at least partially disrupting communication along the neural        fibers via the energy delivery element; and    -   removing the energy delivery element and catheter from the        patient after treatment,    -   wherein at least partially disrupting communication along the        neural fibers therapeutically reduces one or more of—        -   a tumor growth rate of the primary malignant tumor in the            patient;        -   a frequency of metastasis of the primary malignant tumor;        -   vascularization of the primary malignant tumor; and        -   a number of metastatic tumors derived from the primary            malignant tumor in the patient.

41. The method of example 40 wherein the organ comprising the primarymalignant tumor is the breast, pancreas, liver, colon, prostate, ovaryor kidney.

42. The method of example 1 or example 27, further comprisingadministering a β-blocker to the patient.

43. A method of treating a human patient having an increased risk ofdeveloping cancer, the method comprising:

-   -   intravascularly positioning a neuromodulation assembly adjacent        to a renal nerve of the patient; and    -   at least partially inhibiting sympathetic neural activity in the        renal nerve of the patient via the neuromodulation assembly,    -   wherein at least partially inhibiting sympathetic neural        activity results in a therapeutically beneficial reduction in        one or more measurable physiological parameters corresponding to        the initiation and/or promotion of cancer in the patient.

44. The method of example 43 wherein the human patient has apre-cancerous lesion, has previously had a pre-cancerous lesion, haspreviously been diagnosed with cancer, is in remission from cancer,and/or has a genetic pre-disposition for developing cancer.

45. The method of example 43 or example 44 wherein at least partiallyinhibiting sympathetic neural activity in the renal nerve furtherreduces whole body norepinephrine spillover in the patient.

46. The method of any one of examples 43-45 wherein at least partiallyinhibiting sympathetic neural activity in a manner that results in atherapeutically beneficial reduction in one or more measurablephysiological parameters corresponding to the initiation and/orpromotion of cancer in the patient comprises at least one of reducingabnormal cell proliferation, reducing a level of inflammatory cytokinesin the patient, and reducing a level of oncogene activation in cells inthe patient.

IX. CONCLUSION

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments. All references cited herein are incorporated by referenceas if fully set forth herein.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

1-6. (canceled)
 7. A method comprising: intravascularly positioning acatheter adjacent to a first sympathetic nerve innervating a firsttissue site that is proximate to a malignant tumor in a patient;delivering neuromodulation therapy to the first sympathetic nerve viathe catheter to attenuate neural traffic along the first sympatheticnerve; and delivering neuromodulation therapy to a second sympatheticnerve innervating a second tissue site that is at risk of forming ametastatic tumor to attenuate neural traffic along the secondsympathetic nerve, wherein the second sympathetic nerve is associatedwith a different organ or tissue from the first tissue site and does notinnervate the first tissue site.
 8. The method of claim 7, whereindelivering the neuromodulation therapy to at least one of the firstsympathetic nerve or the second sympathetic nerve comprises deliveringablative energy via the catheter.
 9. The method of claim 7, whereindelivering the neuromodulation therapy to at least one of the firstsympathetic nerve or the second sympathetic nerve comprises deliveringelectrical energy via the catheter.
 10. The method of claim 7, whereindelivering the neuromodulation therapy to at least one of the firstsympathetic nerve or the second sympathetic nerve comprises deliveringthermal energy via the catheter.
 11. The method of claim 7, whereindelivering the neuromodulation therapy to at least one of the firstsympathetic nerve or the second sympathetic nerve comprises coolingtissue of the patient.
 12. The method of claim 7, wherein delivering theneuromodulation therapy to at least one of the first sympathetic nerveor the second sympathetic nerve comprises delivering the neuromodulationtherapy via an ultrasound transducer.
 13. The method of claim 7, whereindelivering the neuromodulation therapy to at least one of the firstsympathetic nerve or the second sympathetic nerve comprises delivering achemical to tissue of the patient.
 14. The method of claim 7, whereindelivering neuromodulation therapy to at least one of the firstsympathetic nerve or the second sympathetic nerve comprises deliveringat least one of radio frequency energy, ultrasound energy, laser energy,or microwave energy via a neuromodulation assembly carried by thecatheter.
 15. The method of claim 7, wherein delivery of theneuromodulation therapy to the first sympathetic nerve results in one ormore of: a reduction in a tumor growth rate of the malignant tumor inthe patient; a decrease in a frequency of metastasis of the malignanttumor; at least partial inhibition of vascularization of the malignanttumor; a decrease in number of metastatic tumors derived from themalignant tumor in the patient; or increased effectiveness of achemotherapy agent on cancer cells derived from the malignant tumor. 16.The method of claim 7, wherein there is a delay between deliveringneuromodulation therapy to the first sympathetic nerve and deliveringneuromodulation therapy to the second sympathetic nerve.
 17. The methodof claim 7, wherein delivering neuromodulation therapy to the secondsympathetic nerve reduces a level of whole body norepinephrinespillover.
 18. The method of claim 7, wherein delivering neuromodulationtherapy to the second sympathetic nerve decreases a rate of colonizationof circulating tumor cells at the second tissue site by altering amicroenvironment at the second tissue site to be less habitable tocolonization.
 19. The method of claim 7, wherein attenuating neuraltraffic along the first sympathetic nerve at least one of: decreases anumber of circulating tumor cells in the patient; or inhibits at leastone of lymphatic spread or hematogenous spread of tumor cells from themalignant tumor in the patient.
 20. The method of claim 7, wherein themalignant tumor is located in the breast, colon, kidney, pancreas,liver, prostate, cervix or ovary of the patient.
 21. A methodcomprising: delivering neuromodulation therapy to a first sympatheticnerve via an intravascular neuromodulation assembly to attenuate neuraltraffic along the first sympathetic nerve, wherein the first sympatheticnerve innervates a secondary tissue site that is different than aprimary tissue site that includes a malignant tumor in a patient; anddelivering neuromodulation therapy to the second sympathetic nerve toattenuate neural traffic along the second sympathetic nerve, whereinattenuating neural traffic along the first sympathetic nerve and thesecond sympathetic nerve results in one or more of: a reduction in atumor growth rate of the malignant tumor in the patient, a decrease in afrequency of metastasis of the malignant tumor, at least partialinhibition of vascularization of the malignant tumor, a decrease in anumber of metastatic tumors derived from the malignant tumor in thepatient, a decrease in a rate of colonization of circulating tumor cellsat the secondary tissue site, or increased effectiveness of achemotherapy agent on cancer cells derived from the malignant tumor. 22.The method of claim 21, wherein delivering neuromodulation therapy to atleast one of the first sympathetic nerve or the second sympathetic nervecomprises delivering at least one of radio frequency energy, ultrasoundenergy, laser energy, or microwave energy via the neuromodulationassembly.
 23. The method of claim 21, wherein delivering neuromodulationtherapy to at least one of the first sympathetic nerve or the secondsympathetic nerve comprises cooling tissue of the patient.
 24. Themethod of claim 21, wherein delivering neuromodulation therapy to atleast one of the first sympathetic nerve or the second sympathetic nervecomprises delivering a chemical to tissue of the patient.
 25. The methodof claim 21, wherein delivering neuromodulation therapy to at least oneof the first sympathetic nerve or the second sympathetic nerve comprisesat least partially ablating a respective one of the first sympatheticnerve or the second sympathetic nerve.
 26. The method of claim 21,wherein attenuating neural traffic along the first sympathetic nerve atleast one of reduce muscle sympathetic nerve activity (MSNA) in thepatient or reduces whole body norepinephrine spillover in the patient.